AD-Related N-Terminal Truncated Tau Is Sufficient to Recapitulate In Vivo the Early Perturbations of Human Neuropathology: Implications for Immunotherapy

Abstract

The NH2tau 26–44 aa (i.e., NH2htau) is the minimal biologically active moiety of longer 20–22-kDa NH2-truncated form of human tau—a neurotoxic fragment mapping between 26 and 230 amino acids of full-length protein (htau40)—which is detectable in presynaptic terminals and peripheral CSF from patients suffering from AD and other non-AD neurodegenerative diseases. Nevertheless, whether its exogenous administration in healthy nontransgenic mice is able to elicit a neuropathological phenotype resembling human tauopathies has not been yet investigated. We explored the in vivo effects evoked by subchronic intracerebroventricular (i.c.v.) infusion of NH2htau or its reverse counterpart into two lines of young (2-month-old) wild-type mice (C57BL/6 and B6SJL). Six days after its accumulation into hippocampal parenchyma, significant impairment in memory/learning performance was detected in NH2htau-treated group in association with reduced synaptic connectivity and neuroinflammatory response. Compromised short-term plasticity in paired-pulse facilitation paradigm (PPF) was detected in the CA3/CA1 synapses from NH2htau-impaired animals along with downregulation in calcineurin (CaN)-stimulated pCREB/c-Fos pathway(s). Importantly, these behavioral, synaptotoxic, and neuropathological effects were independent from the genetic background, occurred prior to frank neuronal loss, and were specific because no alterations were detected in the control group infused with its reverse counterpart. Finally, a 2.0-kDa peptide which biochemically and immunologically resembles the injected NH2htau was endogenously detected in vivo, being present in hippocampal synaptosomal preparations from AD subjects. Given that the identification of the neurotoxic tau species is mandatory to develop a more effective tau-based immunological approach, our evidence can have important translational implications for cure of human tauopathies.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Abbreviations

CSF:

Cerebrospinal fluid

AD:

Alzheimer’s disease

APP:

Amyloid precursor protein

i.c.v.:

Intracerebroventricular

mAb:

Monoclonal antibody

NO:

Novel object

FO:

Familiar object

NOR:

Novel object recognition

vGlut1:

Vesicular glutamate transporter 1

SNAP-25:

Synaptosomal-associated protein 25

αSyn:

α-Synuclein

NMDA:

N-methyl-D-aspartate

AMPA:

α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid

GFAP:

Glial fibrillary acidic protein

PPR:

Paired-pulse ratio

HFS:

High-frequency stimulation

CaN:

Calcineurin

CaMKII:

Ca2+-calmodulin-dependent kinase II

CREB:

cAMP response element-binding protein

FTDP-17:

Frontotemporal dementia with parkinsonism-17

GAPDH:

Glyceraldehyde 3-phosphate dehydrogenase

fEPSPs:

Field excitatory postsynaptic potentials

LTP:

Long-term potentiation

SOD1:

Superoxide dismutase 1

NeuN:

Neuron-specific neuronal nuclei

WB:

Western blot

ND:

Nondiseased

DSG:

Disuccinimidyl glutarate

RT:

Room temperature

References

  1. 1.

    Spires-Jones TL, Hyman B (2014) The intersection of amyloid β and tau at synapses in Alzheimer’s disease. Neuron 82:756–771

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  2. 2.

    Davies CA, Mann DM, Sumpter PQ, Yates PO (1987) A quantitative morphometric analysis of the neuronal and synaptic content of the frontal and temporal cortex in patients with Alzheimer’s disease. J Neurol Sci 78:151–164. https://doi.org/10.1016/0022-510X(87)90057-8

    PubMed  CAS  Article  Google Scholar 

  3. 3.

    Scheff SW, Price DA (2001) Alzheimer’s disease-related synapse loss in the cingulate cortex. J Alzheimers Dis 3:495–505

    PubMed  Article  Google Scholar 

  4. 4.

    Scheff SW, Price DA, Schmitt FA et al (2007) Synaptic alterations in CA1 in mild Alzheimer disease and mild cognitive impairment. Neurology 68:1501–1508. https://doi.org/10.1212/01.wnl.0000260698.46517.8f

    PubMed  CAS  Article  Google Scholar 

  5. 5.

    Masliah E (2001) Recent advances in the understanding of the role of synaptic proteins in Alzheimer’s disease and other neurodegenerative disorders. J Alzheimers Dis 3:121–129

    PubMed  CAS  Article  Google Scholar 

  6. 6.

    DeKosky ST, Scheff SW (1990) Synapse loss in frontal cortex biopsies in Alzheimer’s disease: correlation with cognitive severity. Ann Neurol 27:457–464. https://doi.org/10.1002/ana.410270502

    PubMed  CAS  Article  Google Scholar 

  7. 7.

    De-Paula VJ, Radanovic M, Diniz BS, Forlenza OV (2012) Alzheimer’s disease. Subcell Biochem 65:329–352. https://doi.org/10.1007/978-94-007-5416-4_14

    PubMed  CAS  Article  Google Scholar 

  8. 8.

    Huang Y, Mucke L (2012) Alzheimer mechanisms and therapeutic strategies. Cell 148:1204–1222

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  9. 9.

    Pooler AM, Noble W, Hanger DP (2014) A role for tau at the synapse in Alzheimer’s disease pathogenesis. Neuropharmacology 76:1–8

    PubMed  CAS  Article  Google Scholar 

  10. 10.

    Liao D, Miller EC, Teravskis PJ (2014) Tau acts as a mediator for Alzheimer’s disease-related synaptic deficits. Eur J Neurosci 39:1202–1213. https://doi.org/10.1111/ejn.12504

    PubMed  PubMed Central  Article  Google Scholar 

  11. 11.

    Regan P, Whitcomb DJ, Cho K (2016) Physiological and pathophysiological implications of synaptic tau. Neurosci:1–15. https://doi.org/10.1177/1073858416633439

  12. 12.

    Ahmed T, Van der Jeugd A, Blum D et al (2014) Cognition and hippocampal synaptic plasticity in mice with a homozygous tau deletion. Neurobiol Aging 35:2474–2478. https://doi.org/10.1016/j.neurobiolaging.2014.05.005

    PubMed  CAS  Article  Google Scholar 

  13. 13.

    Kimura T, Whitcomb DJ, Jo J et al (2014) Microtubule-associated protein tau is essential for long-term depression in the hippocampus. Philos Trans R Soc L B Biol Sci 369:20130144. https://doi.org/10.1098/rstb.2013.0144

    CAS  Article  Google Scholar 

  14. 14.

    Regan P, Piers T, Yi JH et al (2015) Tau phosphorylation at serine 396 residue is required for hippocampal LTD. J Neurosci 35:4804–4812. https://doi.org/10.1523/JNEUROSCI.2842-14.2015

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  15. 15.

    Bakota L, Ussif A, Jeserich G et al (2017) Systemic and network functions of the microtubule-associated protein tau: Implications for tau-based therapies. Mol Cell Neurosci 84:132-141. https://doi.org/10.1016/j.mcn.2017.03.003

  16. 16.

    Rapoport M, Dawson HN, Binder LI et al (2002) Tau is essential to β-amyloid-induced neurotoxicity. Proc Natl Acad Sci U S A 99:6364–6369. https://doi.org/10.1073/pnas.092136199

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  17. 17.

    Roberson ED, Scearce-Levie K, Palop JJ et al (2007) Reducing endogenous tau ameliorates amyloid β-induced deficits in an Alzheimer’s disease mouse model. Science 316:750–754. https://doi.org/10.1126/science.1141736

    PubMed  CAS  Article  Google Scholar 

  18. 18.

    King ME, Kan HM, Baas PW et al (2006) Tau-dependent microtubule disassembly initiated by prefibrillar β-amyloid. J Cell Biol 175:541–546. https://doi.org/10.1083/jcb.200605187

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  19. 19.

    Vossel KA, Zhang K, Brodbeck J et al (2010) Tau reduction prevents Aβ-induced defects in axonal transport. Science 330:198. https://doi.org/10.1126/science.1194653

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  20. 20.

    Shipton OA, Leitz JR, Dworzak J et al (2011) Tau protein is required for amyloid β-induced impairment of hippocampal long-term potentiation. J Neurosci 31:1688–1692. https://doi.org/10.1523/JNEUROSCI.2610-10.2011

    PubMed  CAS  Article  Google Scholar 

  21. 21.

    Ittner LM, Ke YD, Delerue F et al (2010) Dendritic function of tau mediates amyloid-β toxicity in Alzheimer’s disease mouse models. Cell 142:387–397. https://doi.org/10.1016/j.cell.2010.06.036

    PubMed  CAS  Article  Google Scholar 

  22. 22.

    Hoover BR, Reed MN, Su J et al (2010) Tau mislocalization to dendritic spines mediates synaptic dysfunction independently of neurodegeneration. Neuron 68:1067–1081. https://doi.org/10.1016/j.neuron.2010.11.030

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  23. 23.

    Koffie RM, Hyman BT, Spires-Jones TL (2011) Alzheimer’s disease: synapses gone cold. Mol Neurodegener 6:63. https://doi.org/10.1186/1750-1326-6-63

    PubMed  PubMed Central  Article  Google Scholar 

  24. 24.

    Takahashi RH, Capetillo-Zarate E, Lin MT et al (2010) Co-occurrence of Alzheimer’s disease β-amyloid and tau pathologies at synapses. Neurobiol Aging 31:1145–1152. https://doi.org/10.1016/j.neurobiolaging.2008.07.021

    PubMed  CAS  Article  Google Scholar 

  25. 25.

    Amadoro G, Corsetti V, Atlante A et al (2012) Interaction between NH 2-tau fragment and Aβ in Alzheimer’s disease mitochondria contributes to the synaptic deterioration. Neurobiol Aging 33. https://doi.org/10.1016/j.neurobiolaging.2011.08.001

  26. 26.

    Small SA, Duff K (2008) Linking Aβ and tau in late-onset Alzheimer’s disease: a dual pathway hypothesis. Neuron 60:534–542

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  27. 27.

    Forner S, Baglietto-Vargas D, Martini AC et al (2017) Synaptic impairment in Alzheimer’s disease: a dysregulated symphony. Trends Neurosci 40:347–357

    PubMed  CAS  Article  Google Scholar 

  28. 28.

    Falke E, Nissanov J, Mitchell TW et al (2003) Subicular dendritic arborization in Alzheimer’s disease correlates with neurofibrillary tangle density. Am J Pathol 163:1615–1621. https://doi.org/10.1016/S0002-9440(10)63518-3

    PubMed  PubMed Central  Article  Google Scholar 

  29. 29.

    Ingelsson M, Fukumoto H, Newell KL et al (2004) Early Aβ accumulation and progressive synaptic loss, gliosis, and tangle formation in AD brain. Neurology 62:925–931. https://doi.org/10.1212/01.WNL.0000115115.98960.37

    PubMed  CAS  Article  Google Scholar 

  30. 30.

    Serrano-Pozo A, Mielke ML, Gómez-Isla T et al (2011) Reactive glia not only associates with plaques but also parallels tangles in Alzheimer’s disease. Am J Pathol 179:1373–1384. https://doi.org/10.1016/j.ajpath.2011.05.047

    PubMed  PubMed Central  Article  Google Scholar 

  31. 31.

    Arriagada PV, Marzloff K, Hyman BT (1992) Distribution of Alzheimer-type pathologic changes in nondemented elderly individuals matches the pattern in Alzheimer’s disease. Neurology 42:1681–1688. https://doi.org/10.1212/WNL.42.9.1681

    PubMed  CAS  Article  Google Scholar 

  32. 32.

    Blennow K, Bogdanovic N, Alafuzoff I et al (1996) Synaptic pathology in Alzheimer’s disease: relation to severity of dementia, but not to senile plaques, neurofibrillary tangles, or the ApoE4 allele. J Neural Transm 103:603–618. https://doi.org/10.1007/BF01273157

    PubMed  CAS  Article  Google Scholar 

  33. 33.

    Avila J, de Barreda EG, Fuster-Matanzo A et al (2012) Looking for novel functions of tau. Biochem Soc Trans 40:653–655. https://doi.org/10.1042/BST20120006

    PubMed  CAS  Article  Google Scholar 

  34. 34.

    Avila J, Simón D, Díaz-Hernández M et al (2014) Sources of extracellular tau and its signaling. J Alzheimers Dis 40 Suppl 1:S7-S15. https://doi.org/10.3233/JAD-131832

  35. 35.

    Gómez-Ramos A, Díaz-Hernández M, Cuadros R et al (2006) Extracellular tau is toxic to neuronal cells. FEBS Lett 580:4842–4850. https://doi.org/10.1016/j.febslet.2006.07.078

    PubMed  CAS  Article  Google Scholar 

  36. 36.

    Gómez-Ramos A, Díaz-Hernández M, Rubio A et al (2009) Characteristics and consequences of muscarinic receptor activation by tau protein. Eur Neuropsychopharmacol 19:708–717. https://doi.org/10.1016/j.euroneuro.2009.04.006

    PubMed  CAS  Article  Google Scholar 

  37. 37.

    Fá M, Puzzo D, Piacentini R et al (2016) Extracellular tau oligomers produce an immediate impairment of LTP and memory. Sci Rep 6:19393. https://doi.org/10.1038/srep19393

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  38. 38.

    Pedersen JT, Sigurdsson EM (2015) Tau immunotherapy for Alzheimer’s disease. Trends Mol Med 21:394–402

    PubMed  CAS  Article  Google Scholar 

  39. 39.

    Guillozet-Bongaarts AL, Glajch KE, Libson EG et al (2007) Phosphorylation and cleavage of tau in non-AD tauopathies. Acta Neuropathol 113:513–520. https://doi.org/10.1007/s00401-007-0209-6

    PubMed  CAS  Article  Google Scholar 

  40. 40.

    García-Sierra F, Mondragón-Rodríguez S, Basurto-Islas G (2008) Truncation of tau protein and its pathological significance in Alzheimer’s disease. J Alzheimers Dis 14:401–409

    PubMed  Article  Google Scholar 

  41. 41.

    Horowitz P, Patterson K, Guillozet-Bongaarts A et al (2004) Early N-terminal changes and caspase-6 cleavage of tau in Alzheimer’s disease. J Neurosci 24:7895–7902. https://doi.org/10.1523/JNEUROSCI.1988-04.2004

    PubMed  CAS  Article  Google Scholar 

  42. 42.

    Wang Y, Garg S, Mandelkow E-M, Mandelkow E (2010) Proteolytic processing of tau. Biochem Soc Trans 38:955–961. https://doi.org/10.1042/BST0380955

    PubMed  CAS  Article  Google Scholar 

  43. 43.

    Sokolow S, Henkins KM, Bilousova T et al (2015) Presynaptic C-terminal truncated tau is released from cortical synapses in Alzheimer’s disease. J Neurochem 133:368–379. https://doi.org/10.1111/jnc.12991

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  44. 44.

    Meredith JE, Sankaranarayanan S, Guss V et al (2013) Characterization of novel CSF tau and ptau biomarkers for Alzheimer’s disease. PLoS One 8. https://doi.org/10.1371/journal.pone.0076523

  45. 45.

    Johnson GV, Seubert P, Cox TM et al (1997) The tau protein in human cerebrospinal fluid in Alzheimer’s disease consists of proteolytically derived fragments. J Neurochem 68:430–433. https://doi.org/10.1046/j.1471-4159.1997.68010430.x

    PubMed  CAS  Article  Google Scholar 

  46. 46.

    Portelius E, Hansson SF, Tran AJ et al (2008) Characterization of tau in cerebrospinal fluid using mass spectrometry. J Proteome Res 7:2114–2120. https://doi.org/10.1021/pr7008669

    PubMed  CAS  Article  Google Scholar 

  47. 47.

    Wagshal D, Sankaranarayanan S, Guss V et al (2015) Divergent CSF tau alterations in two common tauopathies: Alzheimer’s disease and progressive supranuclear palsy. J Neurol Neurosurg Psychiatry 86:244–250. https://doi.org/10.1136/jnnp-2014-308004

    PubMed  Article  Google Scholar 

  48. 48.

    Bright J, Hussain S, Dang V et al (2015) Human secreted tau increases amyloid-β production. Neurobiol Aging 36:693–709. https://doi.org/10.1016/j.neurobiolaging.2014.09.007

    PubMed  CAS  Article  Google Scholar 

  49. 49.

    Kanmert D, Cantlon A, Muratore CR et al (2015) C-terminally truncated forms of tau, but not full-length tau or its C-terminal fragments, are released from neurons independently of cell death. J Neurosci 35:10851–10865. https://doi.org/10.1523/JNEUROSCI.0387-15.2015

    PubMed  CAS  Article  Google Scholar 

  50. 50.

    Agadjanyan MG, Zagorski K, Petrushina I et al (2017) Humanized monoclonal antibody armanezumab specific to N-terminus of pathological tau: characterization and therapeutic potency. Mol Neurodegener 12:33. https://doi.org/10.1186/s13024-017-0172-1

    PubMed  PubMed Central  Article  Google Scholar 

  51. 51.

    Yanamandra K, Kfoury N, Jiang H et al (2013) Anti-tau antibodies that block tau aggregate seeding invitro markedly decrease pathology and improve cognition in vivo. Neuron 80:402–414. https://doi.org/10.1016/j.neuron.2013.07.046

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  52. 52.

    Dai CL, Chen X, Kazim SF et al (2015) Passive immunization targeting the N-terminal projection domain of tau decreases tau pathology and improves cognition in a transgenic mouse model of Alzheimer disease and tauopathies. J Neural Transm 122:607–617. https://doi.org/10.1007/s00702-014-1315-y

    PubMed  CAS  Article  Google Scholar 

  53. 53.

    Subramanian S, Savanur G, Madhavadas S (2017) Passive immunization targeting the N-terminal region of phosphorylated tau (residues 68-71) improves spatial memory in okadaic acid induced tauopathy model rats. Biochem Biophys Res Commun 483:585–589. https://doi.org/10.1016/j.bbrc.2016.12.101

    PubMed  CAS  Article  Google Scholar 

  54. 54.

    Yanamandra K, Jiang H, Mahan TE et al (2015) Anti-tau antibody reduces insoluble tau and decreases brain atrophy. Ann Clin Transl Neurol 2:278–288. https://doi.org/10.1002/acn3.176

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  55. 55.

    Dai C, Tung YC, Liu F et al (2017) Tau passive immunization inhibits not only tau but also Aβ pathology. Alzheimers Res Ther 9:1. https://doi.org/10.1186/s13195-016-0227-5

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  56. 56.

    Amadoro G, Corsetti V, Stringaro A et al (2010) A NH2 tau fragment targets neuronal mitochondria at AD synapses: possible implications for neurodegeneration. J Alzheimers Dis 21:445–470. https://doi.org/10.3233/JAD-2010-100120

    PubMed  CAS  Article  Google Scholar 

  57. 57.

    Corsetti V, Florenzano F, Atlante A et al (2014) NH2-truncated human tau induces deregulated mitophagy in neurons by aberrant recruitment of Parkin and UCHL-1: implications in Alzheimer’s disease. Hum Mol Genet 24:3058–3081. https://doi.org/10.1093/hmg/ddv059

    CAS  Article  Google Scholar 

  58. 58.

    Amadoro G, Corsetti V, Sancesario GM et al (2014a) Cerebrospinal fluid levels of a 20–22 kDa NH2 fragment of human tau provide a novel neuronal injury biomarker in Alzheimer’s disease and other dementias. J Alzheimers Dis 42:211–226. https://doi.org/10.3233/JAD-140267

    PubMed  CAS  Article  Google Scholar 

  59. 59.

    Florenzano F, Veronica C, Ciasca G et al (2017) Extracellular truncated tau causes early presynaptic dysfunction associated with Alzheimer’s disease and other tauopathies. Oncotarget. https://doi.org/10.18632/oncotarget.17371

  60. 60.

    Manassero G, Guglielmotto M, Monteleone D et al (2017) Dual mechanism of toxicity for extracellular injection of tau oligomers versus monomers in human tau mice. J Alzheimers Dis 59:743–751. https://doi.org/10.3233/JAD-170298

    PubMed  CAS  Article  Google Scholar 

  61. 61.

    Lasagna-Reeves CA, Castillo-Carranza DL, Sengupta U et al (2011) Tau oligomers impair memory and induce synaptic and mitochondrial dysfunction in wild-type mice. Mol Neurodegener 6:39. https://doi.org/10.1186/1750-1326-6-39

    PubMed  PubMed Central  Article  Google Scholar 

  62. 62.

    Boluda S, Iba M, Zhang B et al (2015) Differential induction and spread of tau pathology in young PS19 tau transgenic mice following intracerebral injections of pathological tau from Alzheimer’s disease or corticobasal degeneration brains. Acta Neuropathol 129:221–237. https://doi.org/10.1007/s00401-014-1373-0

    PubMed  CAS  Article  Google Scholar 

  63. 63.

    Takeda S, Wegmann S, Cho H et al (2015) Neuronal uptake and propagation of a rare phosphorylated high-molecular-weight tau derived from Alzheimer’s disease brain. Nat Commun 6:8490. https://doi.org/10.1038/ncomms9490

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  64. 64.

    Spillantini MG, Goedert M (2013) Tau pathology and neurodegeneration. Lancet Neurol 12:609–622

    PubMed  CAS  Article  Google Scholar 

  65. 65.

    West MJ, Coleman PD, Flood DG, Troncoso JC (1994) Differences in the pattern of hippocampal neuronal loss in normal ageing and Alzheimer’s disease. Lancet 344:769–772. https://doi.org/10.1016/S0140-6736(94)92338-8

    PubMed  CAS  Article  Google Scholar 

  66. 66.

    West MJ, Kawas CH, Martin LJ, Troncoso JC (2006) The CA1 region of the human hippocampus is a hot spot in Alzheimer’s disease. Ann N Y Acad Sci 908:255–259. https://doi.org/10.1111/j.1749-6632.2000.tb06652.x

    Article  Google Scholar 

  67. 67.

    Jagust W (2013) Vulnerable neural systems and the borderland of brain aging and neurodegeneration. Neuron 77:219–234

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  68. 68.

    Honer WG, Dickson DW, Gleeson J, Davies P (1992) Regional synaptic pathology in Alzheimer’s disease. Neurobiol Aging 13:375–382. https://doi.org/10.1016/0197-4580(92)90111-A

    PubMed  CAS  Article  Google Scholar 

  69. 69.

    Scheff SW, Price DA, Schmitt FA, Mufson EJ (2006a) Hippocampal synaptic loss in early Alzheimer’s disease and mild cognitive impairment. Neurobiol Aging 27:1372–1384. https://doi.org/10.1016/j.neurobiolaging.2005.09.012

    PubMed  CAS  Article  Google Scholar 

  70. 70.

    Scheff SW, Price DA (2006b) Alzheimer’s disease-related alterations in synaptic density: neocortex and hippocampus. J Alzheimer’s Dis 9:101–115 Research Support, N.I.H., Extramural Research Support, non-U.S. gov’t review

    Article  Google Scholar 

  71. 71.

    Grayson B, Leger M, Piercy C et al (2015) Assessment of disease-related cognitive impairments using the novel object recognition (NOR) task in rodents. Behav Brain Res 285:176–193. https://doi.org/10.1016/j.bbr.2014.10.025

    PubMed  Article  Google Scholar 

  72. 72.

    Reed JM, Squire LR (1997) Impaired recognition memory in patients with lesions limited to the hippocampal formation. Behav Neurosci 111:667–675. https://doi.org/10.1037/0735-7044.111.4.667

    PubMed  CAS  Article  Google Scholar 

  73. 73.

    Zola SM, Squire LR (2001) Relationship between magnitude of damage to the hippocampus and impaired recognition memory in monkeys. Hippocampus 11:92–98. https://doi.org/10.1002/hipo.1027

    PubMed  CAS  Article  Google Scholar 

  74. 74.

    Shammas SL, Garcia GA, Kumar S et al (2015) A mechanistic model of tau amyloid aggregation based on direct observation of oligomers. Nat Commun 6:7025. https://doi.org/10.1038/ncomms8025

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  75. 75.

    Michel CH, Kumar S, Pinotsi D et al (2014) Extracellular monomeric tau protein is sufficient to initiate the spread of tau protein pathology. J Biol Chem 289:956–967. https://doi.org/10.1074/jbc.M113.515445

    PubMed  CAS  Article  Google Scholar 

  76. 76.

    Usenovic M, Niroomand S, Drolet RE et al (2015) Internalized tau oligomers cause neurodegeneration by inducing accumulation of pathogenic tau in human neurons derived from induced pluripotent stem cells. J Neurosci 35:14234–14250. https://doi.org/10.1523/JNEUROSCI.1523-15.2015

    PubMed  CAS  Article  Google Scholar 

  77. 77.

    Polydoro M, Acker CM, Duff K et al (2009) Age-dependent impairment of cognitive and synaptic function in the htau mouse model of tau pathology. J Neurosci 29 VN-r:10741–10749. https://doi.org/10.1523/JNEUROSCI.1065-09.2009

    CAS  Article  Google Scholar 

  78. 78.

    Lanté F, Chafai M, Raymond EF et al (2015) Sub-chronic glucocorticoid receptor inhibition rescues early episodic memory and synaptic plasticity deficits in a mouse model of Alzheimer’s disease. Neuropsychopharmacology 40:1772–1781. https://doi.org/10.1038/npp.2015.25

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  79. 79.

    Braak H, Braak E (1991) Neuropathological staging of Alzheimer-related changes. Acta Neuropathol 82:239–259. https://doi.org/10.1007/BF00308809

    PubMed  CAS  Article  PubMed Central  Google Scholar 

  80. 80.

    Bengoetxea X, Rodriguez-Perdigon M, Ramirez MJ (2015) Object recognition test for studying cognitive impairments in animal models of Alzheimer’s disease. Front Biosci (Schol Ed) 7:10–29. https://doi.org/10.2741/421

    Article  Google Scholar 

  81. 81.

    Sankaranarayanan S, Barten DM, Vana L et al (2015) Passive immunization with phospho-tau antibodies reduces tau pathology and functional deficits in two distinct mouse tauopathy models. PLoS One 10. https://doi.org/10.1371/journal.pone.0125614

  82. 82.

    Lasagna-Reeves CA, Castillo-Carranza DL, Sengupta U et al (2012) Identification of oligomers at early stages of tau aggregation in Alzheimer’s disease. FASEB J 26:1946–1959. https://doi.org/10.1096/fj.11-199851

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  83. 83.

    Antunes M, Biala G (2012) The novel object recognition memory: neurobiology, test procedure, and its modifications. Cogn Process 13:93–110

    PubMed  CAS  Article  Google Scholar 

  84. 84.

    Leger M, Quiedeville A, Bouet V et al (2013) Object recognition test in mice. Nat Protoc 8:2531–2537. https://doi.org/10.1038/nprot.2013.155

    PubMed  CAS  Article  Google Scholar 

  85. 85.

    deToledo-Morrell L, Stoub TR, Wang C (2007) Hippocampal atrophy and disconnection in incipient and mild Alzheimer's disease. Prog Brain Res 163:741-753

  86. 86.

    Salmon DP, Bondi MW (2009) Neuropsychological assessment of dementia. Annu Rev Psychol 60:257–282. https://doi.org/10.1146/annurev.psych.57.102904.190024

    PubMed  PubMed Central  Article  Google Scholar 

  87. 87.

    Hammond RS, Tull LE, Stackman RW (2004) On the delay-dependent involvement of the hippocampus in object recognition memory. Neurobiol Learn Mem 82:26–34. https://doi.org/10.1016/j.nlm.2004.03.005

    PubMed  Article  Google Scholar 

  88. 88.

    Bucan M, Abel T (2002) The mouse: genetics meets behaviour. Nat Rev Genet 3:114–123. https://doi.org/10.1038/nrg728

    PubMed  CAS  Article  Google Scholar 

  89. 89.

    Holmes A, Wrenn CC, Harris AP et al (2002) Behavioral profiles of inbred strains on novel olfactory, spatial and emotional tests for reference memory in mice. Genes, Brain Behav 1:55–69. https://doi.org/10.1046/j.1601-1848.2001.00005.x

    CAS  Article  Google Scholar 

  90. 90.

    Wolfer DP, Lipp HP (2000) Dissecting the behaviour of transgenic mice: is it the mutation, the genetic background, or the environment? Exp Physiol 85:627–634. https://doi.org/10.1111/j.1469-445X.2000.02095.x

    PubMed  CAS  Article  Google Scholar 

  91. 91.

    Gengler S, Gault VA, Harriott P, Hölscher C (2007) Impairments of hippocampal synaptic plasticity induced by aggregated β-amyloid (25-35) are dependent on stimulation-protocol and genetic background. Exp Brain Res 179:621–630. https://doi.org/10.1007/s00221-006-0819-6

    PubMed  Article  Google Scholar 

  92. 92.

    Karch CM, Jeng AT, Goate AM (2012) Extracellular tau levels are influenced by variability in tau that is associated with tauopathies. J Biol Chem 287:42751–42762. https://doi.org/10.1074/jbc.M112.380642

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  93. 93.

    Knowles WD (1992) Normal anatomy and neurophysiology of the hippocampal-formation. J Clin Neurophysiol 9:252–263. https://doi.org/10.1097/00004691-199204010-00006

    PubMed  CAS  Article  Google Scholar 

  94. 94.

    Lanz TA, Carter DB, Merchant KM (2003) Dendritic spine loss in the hippocampus of young PDAPP and Tg2576 mice and its prevention by the ApoE2 genotype. Neurobiol Dis 13:246–253. https://doi.org/10.1016/S0969-9961(03)00079-2

    PubMed  CAS  Article  Google Scholar 

  95. 95.

    Moolman DL, Vitolo OV, Vonsattel JPG, Shelanski ML (2004) Dendrite and dendritic spine alterations in Alzheimer models. J Neurocytol 33:377–387. https://doi.org/10.1023/B:NEUR.0000044197.83514.64

    PubMed  CAS  Article  Google Scholar 

  96. 96.

    Tsai J, Grutzendler J, Duff K, Gan W-B (2004) Fibrillar amyloid deposition leads to local synaptic abnormalities and breakage of neuronal branches. Nat Neurosci 7:1181–1183. https://doi.org/10.1038/nn1335

    PubMed  CAS  Article  Google Scholar 

  97. 97.

    Spires TL, Molnár Z, Kind PC et al (2005) Activity-dependent regulation of synapse and dendritic spine morphology in developing barrel cortex requires phospholipase C-β1 signalling. Cereb Cortex 15:385–393. https://doi.org/10.1093/cercor/bhh141

    PubMed  Article  Google Scholar 

  98. 98.

    Stern EA, Bacskai BJ, Hickey GA et al (2004) Cortical synaptic integration in vivo is disrupted by amyloid-β plaques. J Neurosci 24:4535–4540. https://doi.org/10.1523/JNEUROSCI.0462-04.2004

    PubMed  CAS  Article  Google Scholar 

  99. 99.

    Knafo S, Alonso-Nanclares L, Gonzalez-Soriano J et al (2009) Widespread changes in dendritic spines in a model of Alzheimer’s disease. Cereb Cortex 19:586–592. https://doi.org/10.1093/cercor/bhn111

    PubMed  CAS  Article  Google Scholar 

  100. 100.

    Knafo S, Venero C, Merino-Serrais P et al (2009) Morphological alterations to neurons of the amygdala and impaired fear conditioning in a transgenic mouse model of Alzheimer’s disease. J Pathol 219:41–51. https://doi.org/10.1002/path.2565

    PubMed  Article  Google Scholar 

  101. 101.

    Terry RD, Masliah E, Salmon DP et al (1991) Physical basis of cognitive alterations in Alzheimer’s disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol 30:572–580. https://doi.org/10.1002/ana.410300410

    PubMed  CAS  Article  Google Scholar 

  102. 102.

    Morrison JH, Hof PR (2002) Selective vulnerability of corticocortical and hippocampal circuits in aging and Alzheimer's disease.Prog Brain Res 136:467-486

  103. 103.

    Counts SE, Nadeem M, Lad SP et al (2006) Differential expression of synaptic proteins in the frontal and temporal cortex of elderly subjects with mild cognitive impairment. J Neuropathol Exp Neurol 65:592–601. https://doi.org/10.1097/00005072-200606000-00007

    PubMed  CAS  Article  Google Scholar 

  104. 104.

    Counts SE, Alldred MJ, Che S et al (2014) Synaptic gene dysregulation within hippocampal CA1 pyramidal neurons in mild cognitive impairment. Neuropharmacology 79:172–179. https://doi.org/10.1016/j.neuropharm.2013.10.018

    PubMed  CAS  Article  Google Scholar 

  105. 105.

    Scheff SW, Price DA (2003)Synaptic pathology in Alzheimer's disease: a review of ultrastructural studies. Neurobiol Aging 24(8):1029-1046

  106. 106.

    Yoshiyama Y, Higuchi M, Zhang B et al (2007) Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron 53:337–351. https://doi.org/10.1016/j.neuron.2007.01.010

    PubMed  CAS  Article  Google Scholar 

  107. 107.

    Eckermann K, Mocanu MM, Khlistunova I et al (2007) The β-propensity of tau determines aggregation and synaptic loss in inducible mouse models of tauopathy. J Biol Chem 282:31755–31765. https://doi.org/10.1074/jbc.M705282200

    PubMed  CAS  Article  Google Scholar 

  108. 108.

    Kopeikina KJ, Polydoro M, Tai HC et al (2013) Synaptic alterations in the rTg4510 mouse model of tauopathy. J Comp Neurol 521:1334–1353. https://doi.org/10.1002/cne.23234

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  109. 109.

    Mocanu M-M, Nissen A, Eckermann K et al (2008) The potential for β-structure in the repeat domain of tau protein determines aggregation, synaptic decay, neuronal loss, and coassembly with endogenous tau in inducible mouse models of tauopathy. J Neurosci 28:737–748. https://doi.org/10.1523/JNEUROSCI.2824-07.2008

    PubMed  CAS  Article  Google Scholar 

  110. 110.

    Alldred MJ, Duff KE, Ginsberg SD (2012) Microarray analysis of CA1 pyramidal neurons in a mouse model of tauopathy reveals progressive synaptic dysfunction. Neurobiol Dis 45:751–762. https://doi.org/10.1016/j.nbd.2011.10.022

    PubMed  CAS  Article  Google Scholar 

  111. 111.

    Crimins JL, Pooler A, Polydoro M et al (2013) The intersection of amyloid β and tau in glutamatergic synaptic dysfunction and collapse in Alzheimer’s disease. Ageing Res Rev 12:757–763

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  112. 112.

    Jadhav S, Cubinkova V, Zimova I et al (2015) Tau-mediated synaptic damage in Alzheimer’s disease. Transl Neurosci 6:214–226. https://doi.org/10.1515/tnsci-2015-0023

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  113. 113.

    Polydoro M, Dzhala VI, Pooler AM et al (2014) Soluble pathological tau in the entorhinal cortex leads to presynaptic deficits in an early Alzheimer’s disease model. Acta Neuropathol 127:257–270. https://doi.org/10.1007/s00401-013-1215-5

    PubMed  CAS  Article  Google Scholar 

  114. 114.

    Dong H, Yuede CM, Coughlan CA et al (2009) Effects of donepezil on amyloid-β and synapse density in the Tg2576 mouse model of Alzheimer’s disease. Brain Res 1303:169–178. https://doi.org/10.1016/j.brainres.2009.09.097

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  115. 115.

    Koffie RM, Meyer-Luehmann M, Hashimoto T et al (2009) Oligomeric amyloid β associates with postsynaptic densities and correlates with excitatory synapse loss near senile plaques. Proc Natl Acad Sci U S A 106:4012–4017. https://doi.org/10.1073/pnas.0811698106

    PubMed  PubMed Central  Article  Google Scholar 

  116. 116.

    Dong H, Martin MV, Chambers S, Csernansky JG (2007) Spatial relationship between synapse loss and β-amyloid deposition in Tg2576 mice. J Comp Neurol 500:311–321. https://doi.org/10.1002/cne.21176

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  117. 117.

    Kaneko T, Fujiyama F, Hioki H (2002) Immunohistochemical localization of candidates for vesicular glutamate transporters in the rat brain. J Comp Neurol 444:39–62. https://doi.org/10.1002/cne.10129

    PubMed  CAS  Article  Google Scholar 

  118. 118.

    Cho KO, Hunt CA, Kennedy MB (1992) The rat brain postsynaptic density fraction contains a homolog of the drosophila discs-large tumor suppressor protein. Neuron 9:929–942. https://doi.org/10.1016/0896-6273(92)90245-9

    PubMed  CAS  Article  Google Scholar 

  119. 119.

    Savioz A, Leuba G, Vallet PG (2014) A framework to understand the variations of PSD-95 expression in brain aging and in Alzheimer’s disease. Ageing Res Rev 18:86–94. https://doi.org/10.1016/j.arr.2014.09.004

    PubMed  CAS  Article  Google Scholar 

  120. 120.

    Leuba G, Savioz A, Vernay A et al (2008) Differential changes in synaptic proteins in the Alzheimer frontal cortex with marked increase in PSD-95 postsynaptic protein. J Alzheimers Dis 15:139–151. https://doi.org/10.3233/JAD-2008-15112

    PubMed  CAS  Article  Google Scholar 

  121. 121.

    Neuman KM, Molina-Campos E, Musial TF et al (2015) Evidence for Alzheimer’s disease-linked synapse loss and compensation in mouse and human hippocampal CA1 pyramidal neurons. Brain Struct Funct 220:3143–3165. https://doi.org/10.1007/s00429-014-0848-z

    PubMed  CAS  Article  Google Scholar 

  122. 122.

    Sze CI, Bi H, Kleinschmidt-Demasters BK et al (2000) Selective regional loss of exocytotic presynaptic vesicle proteins in Alzheimer’s disease brains. J Neurol Sci 175:81–90. https://doi.org/10.1016/S0022-510X(00)00285-9

    PubMed  CAS  Article  Google Scholar 

  123. 123.

    Honer WG (2003)Pathology of presynaptic proteins in Alzheimer's disease: more than simple loss of terminals. Neurobiol Aging 24(8):1047-1062

  124. 124.

    Reddy PH, Mani G, Park BS et al (2005) Differential loss of synaptic proteins in Alzheimer’s disease: implications for synaptic dysfunction. J Alzheimers Dis 7:103–180. https://doi.org/10.1385/NMM:5:2:147

    PubMed  CAS  Article  Google Scholar 

  125. 125.

    King DL, Arendash GW (2002) Maintained synaptophysin immunoreactivity in Tg2576 transgenic mice during aging: correlations with cognitive impairment. Brain Res 926:58–68. https://doi.org/10.1016/S0006-8993(01)03294-2

    PubMed  CAS  Article  Google Scholar 

  126. 126.

    Hoffmann NA, Dorostkar MM, Blumenstock S et al (2013) Impaired plasticity of cortical dendritic spines in P301S tau transgenic mice. Acta Neuropathol Commun 1:82. https://doi.org/10.1186/2051-5960-1-82

    PubMed  PubMed Central  Article  Google Scholar 

  127. 127.

    Mitew S, Kirkcaldie MTK, Dickson TC, Vickers JC (2013) Altered synapses and gliotransmission in Alzheimer’s disease and AD model mice. Neurobiol Aging 34:2341–2351. https://doi.org/10.1016/j.neurobiolaging.2013.04.010

    PubMed  CAS  Article  Google Scholar 

  128. 128.

    Baazaoui N, Flory M, Iqbal K (2017) Synaptic compensation as a probable cause of prolonged mild cognitive impairment in Alzheimer’s disease: implications from a transgenic mouse model of the disease. J Alzheimers Dis 56:1385–1401. https://doi.org/10.3233/JAD-160845

    PubMed  CAS  Article  Google Scholar 

  129. 129.

    Kasai H, Fukuda M, Watanabe S et al (2010) Structural dynamics of dendritic spines in memory and cognition. Trends Neurosci 33:121–129

    PubMed  CAS  Article  Google Scholar 

  130. 130.

    Xu T, Yu X, Perlik AJ et al (2009) Rapid formation and selective stabilization of synapses for enduring motor memories. Nature 462:915–919. https://doi.org/10.1038/nature08389

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  131. 131.

    Yang G, Pan F, Gan WB (2009) Stably maintained dendritic spines are associated with lifelong memories. Nature 462:920–924. https://doi.org/10.1038/nature08577\rnature08577

  132. 132.

    Zempel H, Thies E, Mandelkow E, Mandelkow E-M (2010) A oligomers cause localized Ca2+ elevation, missorting of endogenous tau into dendrites, tau phosphorylation, and destruction of microtubules and spines. J Neurosci 30:11938–11950. https://doi.org/10.1523/JNEUROSCI.2357-10.2010

    PubMed  CAS  Article  Google Scholar 

  133. 133.

    Jackson JS, Witton J, Johnson JD et al (2017) Altered synapse stability in the early stages of tauopathy. Cell Rep 18:3063–3068. https://doi.org/10.1016/j.celrep.2017.03.013

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  134. 134.

    Perez-Cruz C, Nolte MW, van Gaalen MM et al (2011) Reduced spine density in specific regions of CA1 pyramidal neurons in two transgenic mouse models of Alzheimer’s disease. J Neurosci 31:3926–3934. https://doi.org/10.1523/JNEUROSCI.6142-10.2011

    PubMed  CAS  Article  Google Scholar 

  135. 135.

    Ricobaraza A, Cuadrado-Tejedor M, Marco S et al (2012) Phenylbutyrate rescues dendritic spine loss associated with memory deficits in a mouse model of Alzheimer disease. Hippocampus 22:1040–1050. https://doi.org/10.1002/hipo.20883

    PubMed  CAS  Article  Google Scholar 

  136. 136.

    Xu H, Rösler TW, Carlsson T et al (2014) Memory deficits correlate with tau and spine pathology in P301S MAPT transgenic mice. Neuropathol Appl Neurobiol 40:833–843. https://doi.org/10.1111/nan.12160

    PubMed  CAS  Article  Google Scholar 

  137. 137.

    Rocher AB, Crimins JL, Amatrudo JM et al (2010) Structural and functional changes in tau mutant mice neurons are not linked to the presence of NFTs. Exp Neurol 223:385–393. https://doi.org/10.1016/j.expneurol.2009.07.029

    PubMed  CAS  Article  Google Scholar 

  138. 138.

    Spires-Jones TL, Meyer-Luehmann M, Osetek JD et al (2007) Impaired spine stability underlies plaque-related spine loss in an Alzheimer’s disease mouse model. Am J Pathol 171:1304–1311. https://doi.org/10.2353/ajpath.2007.070055

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  139. 139.

    Bittner T, Burgold S, Dorostkar MM et al (2012) Amyloid plaque formation precedes dendritic spine loss. Acta Neuropathol 124:797–807. https://doi.org/10.1007/s00401-012-1047-8

    PubMed  PubMed Central  Article  Google Scholar 

  140. 140.

    Knobloch M, Mansuy IM (2008) Dendritic spine loss and synaptic alterations in Alzheimer’s disease. Mol Neurobiol 37:73–82

    PubMed  CAS  Article  Google Scholar 

  141. 141.

    Holtmaat A, Svoboda K (2009) Experience-dependent structural synaptic plasticity in the mammalian brain. Nat Rev Neurosci 10:647–658. https://doi.org/10.1038/nrn2721

    PubMed  CAS  Article  Google Scholar 

  142. 142.

    Moriyama K, Nishida E, Yonezawa N et al (1990) Destrin, a mammalian actin-depolymerizing protein, is closely related to cofilin. Cloning and expression of porcine brain destrin cDNA. J Biol Chem 265:5768–5773

    PubMed  CAS  Google Scholar 

  143. 143.

    Yahara I, Aizawa H, Moriyama K et al (1996) A role of cofilin/destrin in reorganization of actin cytoskeleton in response to stresses and cell stimuli. Cell Struct Funct 21:421–424. https://doi.org/10.1247/csf.21.421

    PubMed  CAS  Article  Google Scholar 

  144. 144.

    Carlier MF, Laurent V, Santolini J et al (1997) Actin depolymerizing factor (ADF/cofilin) enhances the rate of filament turnover: implication in actin-based motility. J Cell Biol 136:1307–1322. https://doi.org/10.1083/jcb.136.6.1307

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  145. 145.

    Lappalainen P, Drubin DG (1997) Cofilin promotes rapid actin filament turnover in vivo. Nature 388:78–82. https://doi.org/10.1038/40418

    PubMed  CAS  Article  Google Scholar 

  146. 146.

    Welch MD, Mallavarapu A, Rosenblatt J, Mitchison TJ (1997) Actin dynamics in vivo. Curr Opin Cell Biol 9:54–61

    PubMed  CAS  Article  Google Scholar 

  147. 147.

    Ono S (2007) Mechanism of depolymerization and severing of actin filaments and its significance in cytoskeletal dynamics. Int Rev Cytol 258:1–82

    PubMed  CAS  Article  Google Scholar 

  148. 148.

    Ohashi K (2015) Roles of cofilin in development and its mechanisms of regulation. Develop Growth Differ 57:275–290

    CAS  Article  Google Scholar 

  149. 149.

    Carlisle HJ, Kennedy MB (2005) Spine architecture and synaptic plasticity. Trends Neurosci 28:182–187

    PubMed  CAS  Article  Google Scholar 

  150. 150.

    Tada T, Sheng M (2006) Molecular mechanisms of dendritic spine morphogenesis. Curr Opin Neurobiol 16:95–101

    PubMed  CAS  Article  Google Scholar 

  151. 151.

    Henriques AG, Oliveira JM, Carvalho LP, da Cruz e Silva OAB (2015) Aβ influences cytoskeletal signaling cascades with consequences to Alzheimer’s disease. Mol Neurobiol 52:1391–1407

    PubMed  CAS  Article  Google Scholar 

  152. 152.

    Mizuno K (2013) Signaling mechanisms and functional roles of cofilin phosphorylation and dephosphorylation. Cell Signal 25:457–469

    PubMed  CAS  Article  Google Scholar 

  153. 153.

    Sydow A, Hochgräfe K, Könen S et al (2016) Age-dependent neuroinflammation and cognitive decline in a novel Ala152Thr-tau transgenic mouse model of PSP and AD. Acta Neuropathol Commun 4:17. https://doi.org/10.1186/s40478-016-0281-z

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  154. 154.

    Wes PD, Easton A, Corradi J et al (2014) Tau overexpression impacts a neuroinflammation gene expression network perturbed in Alzheimer’s disease. PLoS One 9. https://doi.org/10.1371/journal.pone.0106050

  155. 155.

    Leyns CEG, Holtzman DM (2017) Glial contributions to neurodegeneration in tauopathies. Mol Neurodegener 12:50. https://doi.org/10.1186/s13024-017-0192-x

    PubMed  PubMed Central  Article  Google Scholar 

  156. 156.

    Harris JA, Koyama A, Maeda S et al (2012) Human P301L-mutant tau expression in mouse entorhinal-hippocampal network causes tau aggregation and presynaptic pathology but no cognitive deficits. PLoS One 7. https://doi.org/10.1371/journal.pone.0045881

  157. 157.

    Erez H, Shemesh OA, Spira ME (2014) Rescue of tau-induced synaptic transmission pathology by paclitaxel. Front Cell Neurosci 8:34. https://doi.org/10.3389/fncel.2014.00034

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  158. 158.

    Decker JM, Krüger L, Sydow A et al (2015) Pro-aggregant tau impairs mossy fiber plasticity due to structural changes and Ca++ dysregulation. Acta Neuropathol Commun 3:23. https://doi.org/10.1186/s40478-015-0193-3

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  159. 159.

    Moreno H, Choi S, Yu E et al (2011) Blocking effects of human tau on squid giant synapse transmission and its prevention by T-817 MA. Front Synaptic Neurosci. https://doi.org/10.3389/fnsyn.2011.00003

  160. 160.

    Moreno H, Morfini G, Buitrago L et al (2016) Tau pathology-mediated presynaptic dysfunction. Neuroscience 325:30–38. https://doi.org/10.1016/j.neuroscience.2016.03.044

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  161. 161.

    Tai H-C, Wang BY, Serrano Pozo A et al (2014) Frequent and symmetric deposition of misfolded tau oligomers within presynaptic and postsynaptic terminals in Alzheimer’s disease. Acta Neuropathol Commun 2:146. https://doi.org/10.1186/s40478-014-0146-2

    PubMed  PubMed Central  Article  Google Scholar 

  162. 162.

    Zhou L, Mcinnes J, Wierda K et al (2017) Tau association with synaptic vesicles causes presynaptic dysfunction. Nat Commun 8:1–29. https://doi.org/10.1038/ncomms15295

    Article  Google Scholar 

  163. 163.

    Manabe T, Wyllie DJ, Perkel DJ, Nicoll RA (1993) Modulation of synaptic transmission and long-term potentiation: effects on paired pulse facilitation and EPSC variance in the CA1 region of the hippocampus. J Neurophysiol 70:1451–1459

    PubMed  CAS  Article  Google Scholar 

  164. 164.

    Debanne D, Guérineau NC, Gähwiler BH, Thompson SM (1996) Paired-pulse facilitation and depression at unitary synapses in rat hippocampus: quantal fluctuation affects subsequent release. J Physiol 491:163–176. https://doi.org/10.1113/jphysiol.1996.sp021204

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  165. 165.

    Dobrunz LE, Stevens CF (1997) Heterogeneity of release probability, facilitation, and depletion at central synapses. Neuron 18:995–1008. https://doi.org/10.1016/S0896-6273(00)80338-4

    PubMed  CAS  Article  Google Scholar 

  166. 166.

    Dobrunz LE, Huang EP, Stevens CF (1997) Very short-term plasticity in hippocampal synapses. Proc Natl Acad Sci U S A 94:14843–14847

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  167. 167.

    Thomson AM (2000) Facilitation, augmentation and potentiation at central synapses. Trends Neurosci 23:305–312

    PubMed  CAS  Article  Google Scholar 

  168. 168.

    Zucker RS, Regehr WG (2002) Short-term synaptic plasticity. Annu Rev Physiol 64:355–405. https://doi.org/10.1146/annurev.physiol.64.092501.114547

    PubMed  CAS  Article  Google Scholar 

  169. 169.

    Bliss T, Collingridge G (1993) A synaptic model of memory: long-term potentiation in the hippocampus. Nature 361:31–39

    PubMed  CAS  Article  Google Scholar 

  170. 170.

    Bezprozvanny I, Mattson MP (2008) Neuronal calcium mishandling and the pathogenesis of Alzheimer’s disease. Trends Neurosci 31:454–463

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  171. 171.

    Berridge MJ (2011) Calcium signalling and Alzheimer’s disease. Neurochem Res 36:1149–1156

    PubMed  CAS  Article  Google Scholar 

  172. 172.

    Popugaeva E, Pchitskaya E, Bezprozvanny I (2017) Dysregulation of neuronal calcium homeostasis in Alzheimer’s disease—a therapeutic opportunity? Biochem Biophys Res Commun 483:998–1004

    PubMed  CAS  Article  Google Scholar 

  173. 173.

    Bezprozvanny I, Hiesinger PR (2013) The synaptic maintenance problem: membrane recycling, Ca2+ homeostasis and late onset degeneration. Mol Neurodegener 8:1–14. https://doi.org/10.1186/1750-1326-8-23

    CAS  Article  Google Scholar 

  174. 174.

    Ghosh A, Giese KP (2015) Calcium/calmodulin-dependent kinase II and Alzheimer’s disease. Mol Brain 8:78. https://doi.org/10.1186/s13041-015-0166-2

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  175. 175.

    Deisseroth K, Mermelstein PG, Xia H, Tsien RW (2003) Signaling from synapse to nucleus: the logic behind the mechanisms. Curr Opin Neurobiol 13:354–365

    PubMed  CAS  Article  Google Scholar 

  176. 176.

    Wayman GA, Lee YS, Tokumitsu H et al (2008) Calmodulin-kinases: modulators of neuronal development and plasticity. Neuron 59:914–931

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  177. 177.

    Mohmmad Abdul H, Baig I, LeVine H et al (2011) Proteolysis of calcineurin is increased in human hippocampus during mild cognitive impairment and is stimulated by oligomeric Aβ in primary cell culture. Aging Cell 10:103–113. https://doi.org/10.1111/j.1474-9726.2010.00645.x

    PubMed  CAS  Article  Google Scholar 

  178. 178.

    D’Amelio M, Cavallucci V, Middei S et al (2011) Caspase-3 triggers early synaptic dysfunction in a mouse model of Alzheimer’s disease. Nat Neurosci 14:69–76. https://doi.org/10.1038/nn.2709

    PubMed  CAS  Article  Google Scholar 

  179. 179.

    Reese LC, Zhang WR, Dineley KT et al (2008) Selective induction of calcineurin activity and signaling by oligomeric amyloid β. Aging Cell 7:824–835. https://doi.org/10.1111/j.1474-9726.2008.00434.x

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  180. 180.

    Reese LC, Laezza F, Woltjer R, Taglialatela G (2011) Dysregulated phosphorylation of Ca(2+)/calmodulin-dependent protein kinase II-α in the hippocampus of subjects with mild cognitive impairment and Alzheimer’s disease. J Neurochem 119:791–804. https://doi.org/10.1111/j.1471-4159.2011.07447.x

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  181. 181.

    Dineley KT, Hogan D, Zhang WR, Taglialatela G (2007) Acute inhibition of calcineurin restores associative learning and memory in Tg2576 APP transgenic mice. Neurobiol Learn Mem 88:217–224. https://doi.org/10.1016/j.nlm.2007.03.010

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  182. 182.

    Lian Q, Ladner CJ, Magnuson D, Lee JM (2001) Selective changes of calcineurin (protein phosphatase 2B) activity in Alzheimer’s disease cerebral cortex. Exp Neurol 167:158–165. https://doi.org/10.1006/exnr.2000.7534

    PubMed  CAS  Article  Google Scholar 

  183. 183.

    Cavallucci V, Berretta N, Nobili A et al (2013) Calcineurin inhibition rescues early synaptic plasticity deficits in a mouse model of Alzheimer’s disease. NeuroMolecular Med 15:541–548. https://doi.org/10.1007/s12017-013-8241-2

    PubMed  CAS  Article  Google Scholar 

  184. 184.

    Smith DL, Pozueta J, Gong B et al (2009) Reversal of long-term dendritic spine alterations in Alzheimer disease models. Proc Natl Acad Sci U S A 106:16877–16882. https://doi.org/10.1073/pnas.0908706106

    PubMed  PubMed Central  Article  Google Scholar 

  185. 185.

    Lelos MJ, Good MA (2012) C-fos expression reveals aberrant neural network activity during cued fear conditioning in APPswe transgenic mice. Neurobiol Learn Mem 98:1–11. https://doi.org/10.1016/j.nlm.2012.03.001

    PubMed  CAS  Article  Google Scholar 

  186. 186.

    Lelos MJ, Good MA (2014) β-Amyloid pathology alters neural network activation during retrieval of contextual fear memories in a mouse model of Alzheimer’s disease. Eur J Neurosci 39:1690–1703. https://doi.org/10.1111/ejn.12527

    PubMed  Article  Google Scholar 

  187. 187.

    Saura CA (2012) CREB-regulated transcription coactivator 1-dependent transcription in Alzheimer’s disease mice. Neurodegener Dis 10:250–252. https://doi.org/10.1159/000333341

    PubMed  CAS  Article  Google Scholar 

  188. 188.

    Burlot MA, Braudeau J, Michaelsen-Preusse K et al (2015) Cholesterol 24-hydroxylase defect is implicated in memory impairments associated with alzheimer-like tau pathology. Hum Mol Genet 24:5965–5976. https://doi.org/10.1093/hmg/ddv268

    PubMed  CAS  Article  Google Scholar 

  189. 189.

    Fox LM, William CM, Adamowicz DH et al (2011) Soluble tau species, not neurofibrillary aggregates, disrupt neural system integration in a tau transgenic model. J Neuropathol Exp Neurol 70:588–595. https://doi.org/10.1097/NEN.0b013e318220a658

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  190. 190.

    Minatohara K, Akiyoshi M, Okuno H (2016) Role of immediate-early genes in synaptic plasticity and neuronal ensembles underlying the memory trace. Front Mol Neurosci 8:78. https://doi.org/10.3389/fnmol.2015.00078

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  191. 191.

    Benito E, Barco A (2015) The neuronal activity-driven transcriptome. Mol Neurobiol 51:1071–1088

    PubMed  CAS  Article  Google Scholar 

  192. 192.

    Rajbhandari AK, Zhu R, Adling C et al (2016) Graded fear generalization enhances the level of cfos-positive neurons specifically in the basolateral amygdala. J Neurosci Res 94:1393–1399. https://doi.org/10.1002/jnr.23947

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  193. 193.

    Hardingham GE, Arnold FJ, Bading H (2001) Nuclear calcium signaling controls CREB-mediated gene expression triggered by synaptic activity. Nat Neurosci 4:261–267. https://doi.org/10.1038/85109

    PubMed  CAS  Article  Google Scholar 

  194. 194.

    Mantamadiotis T, Lemberger T, Bleckmann SC et al (2002) Disruption of CREB function in brain leads to neurodegeneration. Nat Genet 31:47–54. https://doi.org/10.1038/ng882

    PubMed  CAS  Article  Google Scholar 

  195. 195.

    Yamamoto-Sasaki M, Ozawa H, Saito T et al (1999) Impaired phosphorylation of cyclic AMP response element binding protein in the hippocampus of dementia of the Alzheimer type. Brain Res 824:300–303. https://doi.org/10.1016/S0006-8993(99)01220-2

    PubMed  CAS  Article  Google Scholar 

  196. 196.

    Peng C, Hong X, Chen W et al (2017) Melatonin ameliorates amygdala-dependent emotional memory deficits in Tg2576 mice by up-regulating the CREB/c-Fos pathway. Neurosci Lett 638:76–82. https://doi.org/10.1016/j.neulet.2016.11.066

    PubMed  CAS  Article  Google Scholar 

  197. 197.

    Sarkar S, Jun S, Rellick S et al (2016) Expression of microRNA-34a in Alzheimer’s disease brain targets genes linked to synaptic plasticity, energy metabolism, and resting state network activity. Brain Res 1646:139–151. https://doi.org/10.1016/j.brainres.2016.05.026

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  198. 198.

    Wilson EN, Abela AR, Do Carmo S et al (2017) Intraneuronal amyloid β accumulation disrupts hippocampal CRTC1-dependent gene expression and cognitive function in a rat model of Alzheimer disease. Cereb Cortex 27(2):1501–1511. https://doi.org/10.1093/cercor/bhv332

    PubMed  PubMed Central  Article  Google Scholar 

  199. 199.

    Sun P, Enslen H, Myung PS, Maurer RA (1994) Differential activation of CREB by Ca2+/calmodulin-dependent protein kinases type II and type IV involves phosphorylation of a site that negatively regulates activity. Genes Dev 8:2527–2539. https://doi.org/10.1101/GAD.8.21.2527

    PubMed  CAS  Article  Google Scholar 

  200. 200.

    Sheng M, Thompson MA, Greenberg ME (1991) CREB: a Ca(2+)-regulated transcription factor phosphorylated by calmodulin-dependent kinases. Science (80-)252:1427–1430. https://doi.org/10.1126/science.1646483

  201. 201.

    Dash PK, Karl KA, Colicos MA et al (1991) cAMP response element-binding protein is activated by Ca2+/calmodulin- as well as cAMP-dependent protein kinase. Proc Natl Acad Sci U S A 88:5061–5065. https://doi.org/10.1073/pnas.88.11.5061

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  202. 202.

    Ginty DD, Bonni A, Greenberg ME (1994) Nerve growth factor activates a Ras-dependent protein kinase that stimulates c-fos transcription via phosphorylation of CREB. Cell 77:713–725. https://doi.org/10.1016/0092-8674(94)90055-8

    PubMed  Article  Google Scholar 

  203. 203.

    Alberini CM (2009) Transcription factors in long-term memory and synaptic plasticity. Physiol Rev:121–145. https://doi.org/10.1152/physrev.00017.2008

  204. 204.

    Flavell SW, Greenberg ME (2008) Signaling mechanisms linking neuronal activity to gene expression and plasticity of the nervous system. Annu Rev Neurosci 31:563–590. https://doi.org/10.1146/annurev.neuro.31.060407.125631

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  205. 205.

    Fleischmann A, Hvalby O, Jensen V et al (2003) Impaired long-term memory and NR2A-type NMDA receptor-dependent synaptic plasticity in mice lacking c-Fos in the CNS. J Neurosci 23:9116–9122

    PubMed  CAS  Article  Google Scholar 

  206. 206.

    Amadoro G, Corsetti V, Florenzano F et al (2014b) AD-linked, toxic NH2 human tau affects the quality control of mitochondria in neurons. Neurobiol Dis 62:489–507. https://doi.org/10.1016/j.nbd.2013.10.018 Erratum in: Neurobiol Dis. 2015 Feb; 74:102–3

    PubMed  CAS  Article  Google Scholar 

  207. 207.

    Canu N, Dus L, Barbato C et al (1998) Tau cleavage and dephosphorylation in cerebellar granule neurons undergoing apoptosis. J Neurosci 18:7061–7074

    PubMed  CAS  Article  Google Scholar 

  208. 208.

    Amadoro G, Serafino AL, Barbato C et al (2004) Role of N-terminal tau domain integrity on the survival of cerebellar granule neurons. Cell Death Differ 11:217–230. https://doi.org/10.1038/sj.cdd.4401314

    PubMed  CAS  Article  Google Scholar 

  209. 209.

    Corsetti V, Amadoro G, Gentile A et al (2008) Identification of a caspase-derived N-terminal tau fragment in cellular and animal Alzheimer’s disease models. Mol Cell Neurosci 38:381–392. https://doi.org/10.1016/j.mcn.2008.03.011

    PubMed  CAS  Article  Google Scholar 

  210. 210.

    Park S-Y, Ferreira A (2005) The generation of a 17 kDa neurotoxic fragment: an alternative mechanism by which tau mediates beta-amyloid-induced neurodegeneration. J Neurosci 25:5365–5375. https://doi.org/10.1523/JNEUROSCI.1125-05.2005

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  211. 211.

    Reinecke JB, DeVos SL, McGrath JP et al (2011) Implicating calpain in tau-mediated toxicity in vivo. PLoS One:6. https://doi.org/10.1371/journal.pone.0023865

  212. 212.

    Ferreira A, Bigio EH (2011) Calpain-mediated tau cleavage: a mechanism leading to neurodegeneration shared by multiple tauopathies. Mol Med 17:676–685. https://doi.org/10.2119/molmed.2010.00220

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  213. 213.

    Vintilescu CR, Afreen S, Rubino AE, Ferreira A (2016) The neurotoxic tau45-230 fragment accumulates in upper and lower motor neurons in amyotrophic lateral sclerosis subjects. Mol Med 22:477–486. https://doi.org/10.2119/molmed.2016.00095

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  214. 214.

    Amadoro G, Ciotti MT, Costanzi M et al (2006) NMDA receptor mediates tau-induced neurotoxicity by calpain and ERK/MAPK activation. Proc Natl Acad Sci U S A 103:2892–2897. https://doi.org/10.1073/pnas.0511065103

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  215. 215.

    Barthélemy NR, Fenaille F, Hirtz C et al (2016) Tau protein quantification in human cerebrospinal fluid by targeted mass spectrometry at high sequence coverage provides insights into its primary structure heterogeneity. J Proteome Res 15:667–676. https://doi.org/10.1021/acs.jproteome.5b01001

    PubMed  CAS  Article  Google Scholar 

  216. 216.

    Dettmer U, Newman AJ, Luth ES et al (2013) In vivo cross-linking reveals principally oligomeric forms of α-synuclein and β-synuclein in neurons and non-neural cells. J Biol Chem 288:6371–6385. https://doi.org/10.1074/jbc.M112.403311

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  217. 217.

    Fauvet B, Mbefo MK, Fares MB et al (2012) α-Synuclein in central nervous system and from erythrocytes, mammalian cells, and Escherichia coli exists predominantly as disordered monomer. J Biol Chem 287:15345–15364. https://doi.org/10.1074/jbc.M111.318949

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  218. 218.

    Luth ES, Bartels T, Dettmer U et al (2015) Purification of α-synuclein from human brain reveals an instability of endogenous multimers as the protein approaches purity. Biochemistry 54:279–292. https://doi.org/10.1021/bi501188a

  219. 219.

    Panza F, Solfrizzi V, Seripa D et al (2016) Tau-based therapeutics for Alzheimer’s disease: active and passive immunotherapy. Immunotherapy 8:1119–1134. https://doi.org/10.2217/imt-2016-0019

    PubMed  CAS  Article  Google Scholar 

  220. 220.

    Panza F, Solfrizzi V, Seripa D et al (2016) Tau-centric targets and drugs in clinical development for the treatment of Alzheimer’s disease. Biomed Res Int 2016:3245935. https://doi.org/10.1155/2016/3245935

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  221. 221.

    Bischof GN, Jessen F, Fliessbach K et al (2016) Impact of tau and amyloid burden on glucose metabolism in Alzheimer’s disease. Ann Clin Transl Neurol 3:934–939. https://doi.org/10.1002/acn3.339

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  222. 222.

    Brier MR, Gordon BA, Friedrichsen K et al (2016) Tau and Aβ imaging, CSF measures, and cognition in Alzheimer’s disease. Sci Transl Med 8:338ra66. https://doi.org/10.1126/scitranslmed.aaf2362

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  223. 223.

    Nelson PT, Alafuzoff I, Bigio EH et al (2012) Correlation of Alzheimer disease neuropathologic changes with cognitive status: a review of the literature. J Neuropathol Exp Neurol 71:362–381. https://doi.org/10.1097/NEN.0b013e31825018f7

    PubMed  PubMed Central  Article  Google Scholar 

  224. 224.

    Ossenkoppele R, Schonhaut DR, Schöll M et al (2016) Tau PET patterns mirror clinical and neuroanatomical variability in Alzheimer’s disease. Brain 139:1551–1567. https://doi.org/10.1093/brain/aww027

    PubMed  PubMed Central  Article  Google Scholar 

  225. 225.

    Chételat G (2013) Alzheimer disease: Aβ-independent processes-rethinking preclinical AD. Nat Rev Neurol 9:123–124. https://doi.org/10.1038/nrneurol.2013.21

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  226. 226.

    Jack CR, Knopman DS, Chételat G et al (2016) Suspected non-Alzheimer disease pathophysiology—concept and controversy. Nat Rev Neurol 12:117–124. https://doi.org/10.1038/nrneurol.2015.251

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  227. 227.

    Ferreira ST, Klein WL (2011) The Aβ-oligomer hypothesis for synapse failure and memory loss in Alzheimer’s disease. Neurobiol Learn Mem 96:529–543

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  228. 228.

    Bell KFS, Ducatenzeiler A, Ribeiro-da-Silva A et al (2006) The amyloid pathology progresses in a neurotransmitter-specific manner. Neurobiol Aging 27:1644–1657. https://doi.org/10.1016/j.neurobiolaging.2005.09.034

    PubMed  CAS  Article  Google Scholar 

  229. 229.

    Selkoe DJ, Morris JC, Petersen RC et al (2002) Alzheimer’s disease is a synaptic failure. Science 298:789–791. https://doi.org/10.1126/science.1074069

    PubMed  CAS  Article  Google Scholar 

  230. 230.

    Terry RD (2000) Cell death or synaptic loss in Alzheimer disease. J Neuropathol Exp Neurol 59:1118–1119. https://doi.org/10.1093/jnen/59.12.1118

    PubMed  CAS  Article  Google Scholar 

  231. 231.

    Masliah E, Mallory M, Alford M et al (2001) Altered expression of synaptic proteins occurs early during progression of Alzheimer’s disease. Neurology 56:127–129. https://doi.org/10.1212/WNL.56.1.127

    PubMed  CAS  Article  Google Scholar 

  232. 232.

    Liu F, Iqbal-Grundke I, Iqbal K et al (2005) Truncation and activation of calcineurin A by calpain I in Alzheimer disease brain. J Biol Chem 280:37755–37762. https://doi.org/10.1074/jbc.M507475200

    PubMed  CAS  Article  Google Scholar 

  233. 233.

    Gong B, Vitolo OV, Trinchese F et al (2004) Persistent improvement in synaptic and cognitive functions in an Alzheimer mouse model after rolipram treatment. J Clin Invest 114:1624–1634. https://doi.org/10.1172/JCI200422831

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  234. 234.

    Baloyannis SJ (2009) Dendritic pathology in Alzheimer’s disease. J Neurol Sci 283:153–157. https://doi.org/10.1016/j.jns.2009.02.370

    PubMed  CAS  Article  Google Scholar 

  235. 235.

    Yiu AP, Rashid AJ, Josselyn SA (2011) Increasing CREB function in the CA1 region of dorsal hippocampus rescues the spatial memory deficits in a mouse model of Alzheimer’s disease. Neuropsychopharmacology 36:2169–2186. https://doi.org/10.1038/npp.2011.107

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  236. 236.

    Satoh JI, Tabunoki H, Arima K (2009) Molecular network analysis suggests aberrant CREB-mediated gene regulation in the Alzheimer disease hippocampus. Dis Markers 27:239–252. https://doi.org/10.3233/DMA-2009-0670

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  237. 237.

    el Hachimi KH, Foncin JF (1990) Loss of dendritic spines in Alzheimer’s disease. CRAcadSciIII 311:397–402

    Google Scholar 

  238. 238.

    Ferrer I, Gullotta F (1990) Down’s syndrome and Alzheimer’s disease: dendritic spine counts in the hippocampus. Acta Neuropathol 79:680–685. https://doi.org/10.1007/BF00294247

    PubMed  CAS  Article  Google Scholar 

  239. 239.

    Akiyama H, Barger S, Barnum S et al (2000) Inflammation and Alzheimer’s disease. Neurobiol Aging 21:383–421

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  240. 240.

    Heneka MT, O’Banion MK (2007) Inflammatory processes in Alzheimer’s disease. J Neuroimmunol 184:69–91

    PubMed  CAS  Article  Google Scholar 

  241. 241.

    Acosta C, Anderson HD, Anderson CM (2017) Astrocyte dysfunction in Alzheimer disease. J Neurosci Res 95(12):2430-2447. https://doi.org/10.1002/jnr.24075

  242. 242.

    Perry VH, O’Connor V (2010) The role of microglia in synaptic stripping and synaptic degeneration: a revised perspective. ASN Neuro 2:e00047. https://doi.org/10.1042/AN20100024

    PubMed  Article  Google Scholar 

  243. 243.

    Yin Y, Gao D, Wang Y et al (2016) Tau accumulation induces synaptic impairment and memory deficit by calcineurin-mediated inactivation of nuclear CaMKIV/CREB signaling. Proc Natl Acad Sci 113:E3773–E3781. https://doi.org/10.1073/pnas.1604519113

    PubMed  CAS  Article  Google Scholar 

  244. 244.

    Yang D, Xie Z, Stephenson D et al (2011) Volumetric MRI and MRS provide sensitive measures of Alzheimer’s disease neuropathology in inducible tau transgenic mice (rTg4510). NeuroImage 54:2652–2658. https://doi.org/10.1016/j.neuroimage.2010.10.067

    PubMed  CAS  Article  Google Scholar 

  245. 245.

    Nilsen LH, Rae C, Ittner LM et al (2013) Glutamate metabolism is impaired in transgenic mice with tau hyperphosphorylation. J Cereb Blood Flow Metab 33:684–691. https://doi.org/10.1038/jcbfm.2012.212

    PubMed  CAS  Article  Google Scholar 

  246. 246.

    Crescenzi R, DeBrosse C, Nanga RPR et al (2014) In vivo measurement of glutamate loss is associated with synapse loss in a mouse model of tauopathy. NeuroImage 101:185–192. https://doi.org/10.1016/j.neuroimage.2014.06.067

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  247. 247.

    Liu X, Zeng K, Li M et al (2017) Expression of P301L-hTau in mouse MEC induces hippocampus-dependent memory deficit. Sci Rep 7:3914. https://doi.org/10.1038/s41598-017-04305-4

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  248. 248.

    Fu H, Rodriguez GA, Herman M et al (2017) Tau pathology induces excitatory neuron loss, grid cell dysfunction, and spatial memory deficits reminiscent of early Alzheimer’s disease. Neuron 93:533–541.e5. https://doi.org/10.1016/j.neuron.2016.12.023

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  249. 249.

    Nakamura K, Greenwood A, Binder L et al (2012) Proline isomer-specific antibodies reveal the early pathogenic tau conformation in Alzheimer’s disease. Cell 149:232–244. https://doi.org/10.1016/j.cell.2012.02.016

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  250. 250.

    Boutajangout A, Quartermain D, Sigurdsson EM (2010) Immunotherapy targeting pathological tau prevents cognitive decline in a new tangle mouse model. J Neurosci 30:16559–16566. https://doi.org/10.1523/JNEUROSCI.4363-10.2010

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  251. 251.

    Boutajangout A, Ingadottir J, Davies P, Sigurdsson EM (2011) Passive immunization targeting pathological phospho-tau protein in a mouse model reduces functional decline and clears tau aggregates from the brain. J Neurochem 118:658–667. https://doi.org/10.1111/j.1471-4159.2011.07337.x

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  252. 252.

    Nitta A, Fukuta T, Hasegawa T, Nabeshima T (1997) Continuous infusion of b-amyloid protein into the rat cerebral ventricle induces learning impairment and neuronal and morphological degeneration. Jpn J Pharmacol 73:51–57. https://doi.org/10.1254/jjp.73.51ClearyJP

    PubMed  CAS  Article  Google Scholar 

  253. 253.

    Rohn TT, Rissman RA, Davis MC et al (2002) Caspase-9 activation and caspase cleavage of tau in the Alzheimer’s disease brain. Neurobiol Dis 11:341–354. https://doi.org/10.1006/nbdi.2002.0549

    PubMed  CAS  Article  Google Scholar 

  254. 254.

    Selenica ML, Davtyan H, Housley SB et al (2014) Epitope analysis following active immunization with tau proteins reveals immunogens implicated in tau pathogenesis. J Neuroinflammation 11:152. https://doi.org/10.1186/s12974-014-0152-0

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  255. 255.

    Walker LC, Jucker M (2017) The exceptional vulnerability of humans to Alzheimer’s disease. Trends Mol Med 23:534–545

    PubMed  PubMed Central  Article  Google Scholar 

  256. 256.

    Bevins RA, Besheer J (2006) Object recognition in rats and mice: a one-trial non-matching-to-sample learning task to study “recognition memory”. Nat Protoc 1:1306–1311. https://doi.org/10.1038/nprot.2006.205

    PubMed  Article  PubMed Central  Google Scholar 

  257. 257.

    Akkerman S, Blokland A, Reneerkens O et al (2012) Object recognition testing: methodological considerations on exploration and discrimination measures. Behav Brain Res 232:335–347. https://doi.org/10.1016/j.bbr.2012.03.022

    PubMed  Article  Google Scholar 

  258. 258.

    Nicholls SB, Devos SL, Commins C et al (2017) Characterization of TauC3 antibody and demonstration of its potential to block tau propagation. PLoS One 12. https://doi.org/10.1371/journal.pone.0177914

  259. 259.

    Pignataro A, Borreca A, Ammassari-Teule M et al (2015) CREB regulates experience-dependent spine formation and enlargement in mouse barrel cortex. Neural Plast 2015:651469. https://doi.org/10.1155/2015/651469

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  260. 260.

    Nisticò R, Mango D, Mandolesi G et al (2013) Inflammation subverts hippocampal synaptic plasticity in experimental multiple sclerosis. PLoS One 8. https://doi.org/10.1371/journal.pone.0054666

  261. 261.

    Severini C, Lattanzi R, Maftei D et al (2015) Bv8/prokineticin 2 is involved in Aβ-induced neurotoxicity. Sci Rep 5:15301. https://doi.org/10.1038/srep15301

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  262. 262.

    Rosoklija GB, Petrushevski VM, Stankov A et al (2014) Reliable and durable Golgi staining of brain tissue from human autopsies and experimental animals. J Neurosci Methods 230:20–29. https://doi.org/10.1016/j.jneumeth.2014.04.006

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  263. 263.

    Gibb R, Kolb B (1998) A method for vibratome sectioning of Golgi–Coxnext term stained whole rat brain. J Neurosci Methods 79:1–4. https://doi.org/10.1016/S0165-0270(97)00163-5

    PubMed  CAS  Article  Google Scholar 

  264. 264.

    Leuner B, Falduto J, Shors TJ (2003) Associative memory formation increases the observation of dendritic spines in the hippocampus. J Neurosci 23:659–665

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  265. 265.

    Horner CH, Arbuthnott E (1991) Methods of estimation of spine density—are spines evenly distributed throughout the dendritic field? J Anat 177:179–184

    PubMed  PubMed Central  CAS  Google Scholar 

  266. 266.

    Nabbi A, Riabowol K (2015) Rapid isolation of nuclei from cells in vitro. Cold Spring Harb Protoc 2015:769–772. https://doi.org/10.1101/pdb.prot083733

    PubMed  Article  Google Scholar 

Download references

Acknowledgements

We wish to thank Dott.ssa Francesca Malerba and Dott. Bruno Bruni Ercole for their technical help in 12A12 antibody purification. We are also grateful to Dott. Francesco Valeri and Dott. Francesco Marrocco for their technical help in morphological studies. We finally thank Dott.ssa Antonella Gentile for providing us several antibodies against synaptic and inflammatory markers.

Ethics Approvals

All protocols involving animals were performed in accordance with the guidelines established by the European Communities Council (Directive 2010/63/EU of 22 September 2010). Experiments involving animals were performed in accordance with the relevant approved guidelines and regulations accepted by the Italian Ministry of Health and approved by the Ethical Committee on Animal Experiments of Rome, Italy.

Human brain material was provided via the rapid autopsy program of the Netherlands Brain Bank (NBB), which provides postmortem specimens from clinically well documented and neuropathologically confirmed cases. All research involving them was conducted according to the ethical declaration of the NBB. Ethical approval and written informed consent from the donors or the next of kin were obtained in all cases. For details (ethics statement declarations and subjects’ demographics), see [25, 56].

Funding

This research was supported by Magnetic Diagnostic Assay for neurodegenerative diseases H2020-ICT-2016-2017 “SSI-Smart System Integration” Proposal 732678 SEP 210349930. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Author information

Affiliations

Authors

Contributions

A.B., V.L., S.M., and S.P. performed morphological, biochemical, electrophysiological, and behavioral experiments; V.C. and F.D.V. performed crosslinking experiments on human brain tissue and carried out 12A12 production; M. A-T., R.N., and P.C. contributed through discussions; R.B. provided analytical tools; and G.A. designed the research, conceived and supervised all the experiments, and wrote the manuscript.

Corresponding author

Correspondence to G. Amadoro.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflicts of interest.

Consent for Publication

All authors approve the study described in this report and give their consent for publication.

Electronic Supplementary Material

Suppl. Fig. 1
figure7

Biochemical characterization of the human NH2tau 26–44 (i.e. NH2htau) preparations. An aliquot of NH2htau preparation which was used for in vivo intracerebroventricular (i.c.v.) injection (20 μg) was checked prior to any administration via stereotaxic surgeries by Western blotting on Bis- Tris gel 4–12% resolution gels followed by electroblotting onto a high-performing PVDF transfer membrane. The filter was probed with specific 12A12 monoclonal antibody directed against the extreme N-terminal 26–36 aa of human tau protein. Note that the prevailing molecular form of NH2htau appears to be soluble and monomeric, being lowly-aggregated (dimeric/oligomeric) species migrating <35-50 kDa less abundant. (GIF 96 kb)

Suppl. Fig. 2
figure8

In vivo analysis of neuronal distribution of injected NH2htau into hippocampus. Confocal microscopy analysis of double immunofluorescence with neuron-specific βIII tubulin (green channel) and human-specific NH2 21–36 tau- antibodies (red channel) carried out on CA1 hippocampal sections from B6SJL wild-type (2-month-old) NH2htau- and reverse-injected mice. Nuclei were stained with DAPI (blue channel). Note that the staining of exogenously-applied NH2htau within hippocampal structures is mainly distributed along the neuritic processes (yellow, arrow). Similar results were found from reverse- and NH2htau-injected wild-type C57BL/6 mice. Scale bar: 20 μm. (GIF 187 kb)

Suppl. Fig. 3
figure9

Soluble NH2htau is toxic in vivo to synapses but not lethal to neurons. Western blotting analysis was carried out on equal amounts of total protein extract (50 μg) from hippocampal tissues of reverse- and NH2htau-injected wild-type B6SJL (2-month-old). Immunoblots were probed with antibodies against the active-(cleaved) form of caspase-3 (Asp175). SY5Y cells exposed to 1 μM staurosporine (STS) for 4 h were used as positive control. For normalization of the samples’ loading, β-actin was used. Similar results were found from reverse- and NH2htau-injected wild-type C57BL/6 mice. (GIF 115 kb)

Suppl. Fig. 4
figure10

Neuronal connectivity is severely disrupted in NH2htau-injected mice from wild-type B6SJL genetic background without any significant change in the cell number. A-B): Representative microphotographs (n = 3) of double immunofluorescence and confocal microscopy analysis for presynaptic marker synaptophysin (red channel) and the postsynaptic marker PSD95 (green channel) carried out on CA1 hippocampal sections from wild-type (2-month-old) B6SJL NH2htau- and reverse-injected mice. Nuclei were stained with DAPI (blue channel) (A). The number of intact synaptic boutons (Syn/PSD95-positive puncta, arrow) from the three experimental groups (reverse, NH2htau-injected and age-matched home-cage controls) was also shown (B). Statistically significant differences were calculated by a one-way ANOVA analysis followed by Fisher post hoc test (one-way ANOVA analysis (2,23) = 27.5 Fisher post hoc test home-cage vs NH2htau-injected: **p < 0.01; reverse-injected vs NH2htau-injected: ***p < 0.001). Scale bar: 10 μm. C-D): Representative confocal microscopy images (n = 3) of CA1 hippocampal region from NH2htau- and reverse-injected from wild-type (2-month-old) B6SJL stained for neuron-specific nuclear marker NeuN (C). No statistically difference in the number of NeuN positive neurons (one-way ANOVA analysis, F(2, 23) = 1.62 p = 0.22 Fisher post hoc test reverse- vs NH2htau-injected p = 0.22; home-cage vs NH2htau-injected p = 0.74; reverse-injected vs home-cage 푝=0.08) was calculated among the three analyzed experimental groups (reverse, NH2htau-injected and age-matched home-cage controls) (D). Scale bar: 10 μm. E-F): Representative blots (n = 3) of Western blotting analysis on isolated synaptosomal preparations from hippocampal region of NH2htau- and reverse-injected wild-type B6SJL mice (2-month-old) to assess the content of presynaptic (α-synuclein, syntaxin, synaptosomal-associated protein 25 (SNAP-25), synaptophysin) and postsynaptic proteins (N-Methyl-D-aspartate (NMDA) Receptor subunit NR1, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) metabotropic Receptor subunit mGluR2 and mGluR5). β-actin and GAPDH (glyceraldehyde 3-phosphate dehydrogenase) were used as loading controls (E) and densitometric quantification was shown (F). Values are means of at least three independent experiments and statistically significant differences were calculated by unpaired two-tailed t-Student’s test (*p < 0.05). G-H): Representative examples (G) of Golgi-stained hippocampal CA1 pyramidal neurons showing dendritic segments at low magnification (4X) and high (100X) magnifications to display spines in NH2htau- and reverse-injected wild-type B6SJL mice (2-month-old). Quantification (H) of dendritic spine density was also shown. Values are means of at least three independent experiments and statistically significant differences were calculated by one-way ANOVA analysis followed by Fisher post hoc test (F(2, 23) = 7.4 p = 0.003; reverse- vs NH2htau-injected **p < 0.01; home-cage vs NH2htau-injected: **p < 0.01; home-cage vs reverse p = 0.77). (GIF 487 kb)

Suppl. Fig. 5
figure11

Prominent activation of astrocytes and microglia is also detected in NH2htau- injected wild-type B6SJL mice. A-B): Purified synaptosomal preparations from hippocampal region of NH2htau- and reverse-injected wild-type B6SJL mice (2-month-old) was subjected to SDS-PAGE electrophoresis and Western blotting analysis by filter probing with antibodies against to the phosphorylated (inactive) form of cofilin (Ser-3) and the total cofilin. β-actin and GAPDH (glyceraldehyde 3-phosphate dehydrogenase) were used as loading controls (H) and densitometric quantification was shown (I). Values are means of at least three independent experiments and statistically significant differences were calculated by unpaired two-tailed t-Student’s test (*p < 0.05). C-D): Immunofluorescence followed by confocal microscopy analysis of astrocytes and microglial markers -glial fibrillary acidic protein (GFAP) and Iba1, respectively (green channel)- was carried out on CA1 hippocampal sections from wild-type B6SJL mice (2-month-old) NH2htau- and reverse-injected mice to evaluate the magnitude of neuroinflammatory response. Nuclei were stained with DAPI (blue channel). Notice the extensive reactive gliosis (increased proliferation and morphological changes of astrocytes and microglia) in hippocampal region from NH2htau-infused animals. Scale bar: 50 μm. E-F-G-H): Neuroinflammation processes (activation of astrocytes and microglia) was assessed on hippocampal extracts from NH2htau- and reverse-injected wild-type B6SJL mice (2-month-old) by Western blotting analysis for inflammatory proteins (GFAP, Iba1, E-G respectively). Relative densitometric quantification of intensity signals (F-H) indicates increased levels of GFAP and Iba1 in NH2htau- compared to reverse-injected wild-type C57BL/6 mice (2-month-old). GAPDH serves as loading control. Data are mean +/− S.E.M and statistical significance was calculated by unpaired two-tailed t-Student’s test (***p < 0.001; *p < 0.05). (GIF 507 kb)

Suppl. Fig. 6
figure12

NH2htau-injected mice from B6SJL strains show deficits in presynaptically mediated short-term enhancement of hippocampal neurotransmission. A): Input/output curves as plots of the fEPSP slopes against the corresponding presynaptic fiber volley amplitudes are shown from hippocampal slices of non-transgenic B6SJL (2-month-old) reverse- (n = 9) and NH2htau-injected mice (n = 10). No significant difference (unpaired two-tailed t-Student’s test p > 0.05) was detected between the treated experimental groups which were unaffected in all the analyzed conditions. B): Comparison of paired-pulse facilitation (PPF) in wild-type B6SJL (2-month-old) reverse- (n = 9) and NH2htau-injected mice (n = 10). PPF was induced by pairs of stimuli delivered at increasing interpulse intervals (20, 50, 100, 200, 500 msec). Data are presented as the mean (±SEM) facilitation ratio of the second response relative to the first response. Significant values were detected at 50 and 100 msec interval (unpaired two-tailed t-Student’s test *p < 0.05). C) Time plot of average fEPSP responses showed that no change in magnitude of CA1-LTP was found between 2-month-old wild-type B6SJL reverse- (n = 9) and NH2htau-injected mice (n = 10) (unpaired two-tailed t-Student’s test *p > 0.05). The magnitude of potentiation was measured 50–60 min after the conditioning train. For each condition fEPSP recordings from baseline and 60 min post-HFS were calculated. (GIF 207 kb)

Suppl. Fig. 7
figure13

In vivo NH2htau accumulation induces calcineurin-mediated inactivation of the nuclear CaMKII/CREB/c-Fos signaling in hippocampus of B6SJL injected mice. A-B-C-D-E-F-G-H-I): Hippocampal tissues from a randomly selected subset of behaviourally-trained (1 h after the test acquisition) reverse- (n = 3) and NH2htau-injected (n = 3) wild-type B6SJL (2-month-old) mice were used for cytosol/nuclear protein fractionation from total lysates. Representative Western blotting analysis showing the expression profile of total CaMKII, pCaMKII (A), CN-A full length, CN-A active truncated form (C), total CREB, pCREB (E) and the three 62 kDa, 49 kDa and 41 kDa c-Fos (G) immunoreactive bands in enriched subcellular preparations and relative densitometric quantification (B-D-F-H) are shown. Superoxide dismutase 1 (SOD1) and neuron-specific Neuronal Nuclei (NeuN) proteins were used as cytosolic and nuclear markers, respectively (I). *p < 0.05(unpaired two-tailed t-Student’s test). (GIF 524 kb)

High resolution image (EPS 10154 kb)

High resolution image (EPS 11291 kb)

High resolution image (EPS 1188 kb)

High resolution image (EPS 137862 kb)

High resolution image (EPS 8711 kb)

High resolution image (EPS 1078 kb)

High resolution image (EPS 8085 kb)

ESM 1

Suppl. text Number of independent observations for experimental conditions analyzed in each assay. In the table is reported the number of observations (animals, image fields, protein samples) analyzed in each assay for experimental conditions from independent experiments. (DOCX 15 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Borreca, A., Latina, V., Corsetti, V. et al. AD-Related N-Terminal Truncated Tau Is Sufficient to Recapitulate In Vivo the Early Perturbations of Human Neuropathology: Implications for Immunotherapy. Mol Neurobiol 55, 8124–8153 (2018). https://doi.org/10.1007/s12035-018-0974-3

Download citation

Keywords

  • Tau protein
  • Tauopathies
  • Alzheimer’s disease
  • Tau cleavage
  • Immunotherapy