Advertisement

Neurotherapeutics

, Volume 16, Issue 3, pp 710–724 | Cite as

CYP46A1 Activation by Efavirenz Leads to Behavioral Improvement without Significant Changes in Amyloid Plaque Load in the Brain of 5XFAD Mice

  • Alexey M. Petrov
  • Morrie Lam
  • Natalia Mast
  • Jean Moon
  • Yong Li
  • Erin Maxfield
  • Irina A. PikulevaEmail author
Original Article
  • 400 Downloads

Abstract

Efavirenz, the FDA-approved anti-retroviral medication, is evaluated in the clinical trial in patients with mild cognitive impairment or early dementia due to Alzheimer’s disease. Efavirenz is assessed for activation of cytochrome P450 46A1 (CYP46A1), a CNS-specific enzyme that converts cholesterol to 24-hydroxycholesterol. Cholesterol 24-hydroxylation is the major pathway for brain cholesterol removal, and a mechanism that controls brain cholesterol turnover. The present study tested efavirenz on 5XFAD mice (an Alzheimer’s model) at a very low daily dose of 0.1 mg/kg body weight. Efavirenz treatment started from three months of age, after amyloid plague appearance, and continued for 6 months. This treatment led to CYP46A1 activation in the brain, enhancement of brain cholesterol turnover, behavioral improvements, reduction in microglia activation but increased astrocyte reactivity. The levels of the soluble and insoluble amyloid 40 and 42 peptides were unchanged while the number and area of the dense core amyloid plaques were slightly decreased. The measurements of the brain levels of several pre- and post-synaptic proteins (Munc13-1, PSD-95, gephyrin, synaptophysin, synapsin-1, and calbindin-D28k) suggested efavirenz effect at the synaptic level. Efavirenz treatment in the present work seems to represent a model of behavioral and other improvements independent of the levels of the amyloid peptides and provides insight into potential outcomes of the future clinical trial.

Key Words

CYP46A1 Efavirenz Alzheimer’s disease 24-hydroxycholesterol Astrocytes Microglia Synaptic proteins 

Abbreviations

Amyloid β Peptide

AD

Alzheimer’s Disease

APP

Amyloid Precursor Protein

CS

Conditioned Stimulus

CYP46A1

Cytochrome P450 46A1

EFV

Efavirenz

GABA

Gamma-Aminobutyric Acid

GFAP

Glial Fibrillary Acidic Protein

24HC

24-Hydroxycholesterol

HMGCR

3-Hydroxy-3-Methylglutaryl-CoA Reductase

Iba1

Ionized Calcium Binding Adaptor Molecule 1

LXR

Liver X Receptor

MWM

Morris Water Maze

NMDAR

N-Methyl-D-Aspartate Receptors

PBS

Phosphate Buffer Saline

US

Unconditioned Stimulus

Notes

Acknowledgments

This work was supported in part in by National Institute of General Medical Sciences grant GM062882 (IAP). The authors thank the Visual Sciences Research Center Core Facilities (supported by National Institutes of Health Grant P30 EY11373) for assistance with mouse breeding (Heather Butler and Kathryn Franke), animal genotyping (John Denker), tissue sectioning (Catherine Doller), and microscopy (Anthony Gardella). We are also grateful to Dr. Hiroyuki Arakawa for behavioral testing.

Author Contributions

IAP conceived and designed the study; ML, NM, JM, YL, and EM performed the experiments; IP, NM, AMP, and ML analyzed the data; IAP and AMP wrote the paper; IAP acquired funding.

Compliance with Ethical Standards

Conflict of Interest

The authors declare no conflict of interest.

References

  1. 1.
    Blesa R, Toriyama K, Ueda K, et al (2018). Strategies for Continued Successful Treatment in Patients with Alzheimer's Disease: An Overview of Switching Between Pharmacological Agents. Curr Alzheimer Res 15: 964–974CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Lutjohann D, Breuer O, Ahlborg G, et al (1996). Cholesterol homeostasis in human brain: evidence for an age-dependent flux of 24S-hydroxycholesterol from the brain into the circulation. Proc Natl Acad Sci U S A 93: 9799–9804CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Lund EG, Guileyardo JM, Russell DW (1999). cDNA cloning of cholesterol 24-hydroxylase, a mediator of cholesterol homeostasis in the brain. Proc Natl Acad Sci U S A 96: 7238–7243CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Ramirez DM, Andersson S, Russell DW (2008). Neuronal expression and subcellular localization of cholesterol 24-hydroxylase in the mouse brain. J Comp Neurol 507: 1676–1693CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Meaney S, Bodin K, Diczfalusy U, et al (2002). On the rate of translocation in vitro and kinetics in vivo of the major oxysterols in human circulation: critical importance of the position of the oxygen function. J Lipid Res 43: 2130–2135CrossRefPubMedGoogle Scholar
  6. 6.
    Dietschy JM (2009). Central nervous system: cholesterol turnover, brain development and neurodegeneration. Biol Chem 390: 287–293CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Lund EG, Xie C, Kotti T, et al (2003). Knockout of the cholesterol 24-hydroxylase gene in mice reveals a brain-specific mechanism of cholesterol turnover. J Biol Chem 278: 22980–22988CrossRefPubMedGoogle Scholar
  8. 8.
    Pfrieger FW, Ungerer N (2011). Cholesterol metabolism in neurons and astrocytes. Prog Lipid Res 50: 357–371CrossRefPubMedGoogle Scholar
  9. 9.
    Mast N, Li Y, Linger M, et al (2014). Pharmacologic stimulation of cytochrome P450 46A1 and cerebral cholesterol turnover in mice. J Biol Chem 289: 3529–3538CrossRefPubMedGoogle Scholar
  10. 10.
    Mast N, Saadane A, Valencia-Olvera A, et al (2017). Cholesterol-metabolizing enzyme cytochrome P450 46A1 as a pharmacologic target for Alzheimer's disease. Neuropharmacology 123: 465–476CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Paul SM, Doherty JJ, Robichaud AJ, et al (2013). The major brain cholesterol metabolite 24(S)-hydroxycholesterol is a potent allosteric modulator of N-methyl-D-aspartate receptors. J Neurosci 33: 17290–17300CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Sun MY, Izumi Y, Benz A, et al (2016). Endogenous 24S-hydroxycholesterol modulates NMDAR-mediated function in hippocampal slices. J Neurophysiol 115: 1263–1272CrossRefPubMedGoogle Scholar
  13. 13.
    Kalaany NY, Mangelsdorf DJ (2006). LXRS and FXR: the yin and yang of cholesterol and fat metabolism. Annu Rev Physiol 68: 159–191CrossRefPubMedGoogle Scholar
  14. 14.
    Calkin AC, Tontonoz P (2012). Transcriptional integration of metabolism by the nuclear sterol-activated receptors LXR and FXR. Nat Rev Mol Cell Biol 13: 213–224CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Glass CK, Ogawa S (2006). Combinatorial roles of nuclear receptors in inflammation and immunity. Nat Rev Immunol 6: 44–55CrossRefPubMedGoogle Scholar
  16. 16.
    Chen J, Zacharek A, Cui X, et al (2010). Treatment of stroke with a synthetic liver X receptor agonist, TO901317, promotes synaptic plasticity and axonal regeneration in mice. J Cereb Blood Flow Metab 30: 102–109CrossRefGoogle Scholar
  17. 17.
    Peng Z, Deng B, Jia J, et al (2018). Liver X receptor beta in the hippocampus: A potential novel target for the treatment of major depressive disorder? Neuropharmacology 135: 514–528CrossRefPubMedGoogle Scholar
  18. 18.
    Lutjohann D, Papassotiropoulos A, Bjorkhem I, et al (2000). Plasma 24S-hydroxycholesterol (cerebrosterol) is increased in Alzheimer and vascular demented patients. J Lipid Res 41: 195–198PubMedGoogle Scholar
  19. 19.
    Bretillon L, Siden A, Wahlund LO, et al (2000). Plasma levels of 24S-hydroxycholesterol in patients with neurological diseases. Neurosci Lett 293: 87–90CrossRefPubMedGoogle Scholar
  20. 20.
    Kolsch H, Heun R, Kerksiek A, et al (2004). Altered levels of plasma 24S- and 27-hydroxycholesterol in demented patients. Neurosci Lett 368: 303–308CrossRefPubMedGoogle Scholar
  21. 21.
    Bogdanovic N, Bretillon L, Lund EG, et al (2001). On the turnover of brain cholesterol in patients with Alzheimer's disease. Abnormal induction of the cholesterol-catabolic enzyme CYP46 in glial cells. Neurosci Lett 314: 45–48CrossRefPubMedGoogle Scholar
  22. 22.
    Brown J, 3rd, Theisler C, Silberman S, et al (2004). Differential expression of cholesterol hydroxylases in Alzheimer's disease. J Biol Chem 279: 34674–34681CrossRefPubMedGoogle Scholar
  23. 23.
    Tian G, Kong Q, Lai L, et al (2010). Increased expression of cholesterol 24S-hydroxylase results in disruption of glial glutamate transporter EAAT2 association with lipid rafts: a potential role in Alzheimer's disease. J Neurochem 113: 978–989CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Russell DW, Halford RW, Ramirez DM, et al (2009). Cholesterol 24-hydroxylase: an enzyme of cholesterol turnover in the brain. Annu Rev Biochem 78: 1017–1040CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Hudry E, Van Dam D, Kulik W, et al (2010). Adeno-associated virus gene therapy with cholesterol 24-hydroxylase reduces the amyloid pathology before or after the onset of amyloid plaques in mouse models of Alzheimer's disease. Mol Ther 18: 44–53CrossRefPubMedGoogle Scholar
  26. 26.
    Bryleva EY, Rogers MA, Chang CC, et al (2010). ACAT1 gene ablation increases 24(S)-hydroxycholesterol content in the brain and ameliorates amyloid pathology in mice with AD. Proc Natl Acad Sci U S A 107: 3081–3086CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    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: 5965–5976CrossRefPubMedGoogle Scholar
  28. 28.
    Djelti F, Braudeau J, Hudry E, et al (2015). CYP46A1 inhibition, brain cholesterol accumulation and neurodegeneration pave the way for Alzheimer's disease. Brain 138: 2383–2398CrossRefPubMedGoogle Scholar
  29. 29.
    Ayciriex S, Djelti F, Alves S, et al (2017). Neuronal Cholesterol Accumulation Induced by Cyp46a1 Down-Regulation in Mouse Hippocampus Disrupts Brain Lipid Homeostasis. Front Mol Neurosci 10: 211CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Halford RW, Russell DW (2009). Reduction of cholesterol synthesis in the mouse brain does not affect amyloid formation in Alzheimer's disease, but does extend lifespan. Proc Natl Acad Sci U S A 106: 3502–3506CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Anderson KW, Mast N, Hudgens JW, et al (2016). Mapping of the Allosteric Site in Cholesterol Hydroxylase CYP46A1 for Efavirenz, a Drug That Stimulates Enzyme Activity. J Biol Chem 291: 11876–11886CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Oakley H, Cole SL, Logan S, et al (2006). Intraneuronal beta-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer's disease mutations: potential factors in amyloid plaque formation. J Neurosci 26: 10129–10140CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Hyman BT (2011). Amyloid-dependent and amyloid-independent stages of Alzheimer disease. Arch Neurol 68: 1062–1064CrossRefPubMedGoogle Scholar
  34. 34.
    Karran E, Mercken M, De Strooper B (2011). The amyloid cascade hypothesis for Alzheimer's disease: an appraisal for the development of therapeutics. Nat Rev Drug Discov 10: 698–712CrossRefGoogle Scholar
  35. 35.
    Mast N, Reem R, Bederman I, et al (2011). Cholestenoic Acid is an important elimination product of cholesterol in the retina: comparison of retinal cholesterol metabolism with that in the brain. Invest Ophthalmol Vis Sci 52: 594–603CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Heo GY, Liao WL, Turko IV, et al (2012). Features of the retinal environment which affect the activities and product profile of cholesterol-metabolizing cytochromes P450 CYP27A1 and CYP11A1. Arch Biochem Biophys 518: 119–126CrossRefPubMedGoogle Scholar
  37. 37.
    Schmidt SD, Jiang Y, Nixon RA, et al (2005). Tissue processing prior to protein analysis and amyloid-beta quantitation. Methods Mol Biol 299: 267–278PubMedGoogle Scholar
  38. 38.
    Dickson DW (1997). The pathogenesis of senile plaques. J Neuropathol Exp Neurol 56: 321–339CrossRefPubMedGoogle Scholar
  39. 39.
    Cartagena CM, Ahmed F, Burns MP, et al (2008). Cortical injury increases cholesterol 24S hydroxylase (Cyp46) levels in the rat brain. J Neurotrauma 25: 1087–1098CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Lewis GP, Fisher SK (2003). Up-regulation of glial fibrillary acidic protein in response to retinal injury: its potential role in glial remodeling and a comparison to vimentin expression. Int Rev Cytol 230: 263–290CrossRefPubMedGoogle Scholar
  41. 41.
    Santos AM, Calvente R, Tassi M, et al (2008). Embryonic and postnatal development of microglial cells in the mouse retina. J Comp Neurol 506: 224–239CrossRefPubMedGoogle Scholar
  42. 42.
    Spangenberg EE, Lee RJ, Najafi AR, et al (2016). Eliminating microglia in Alzheimer's mice prevents neuronal loss without modulating amyloid-beta pathology. Brain 139: 1265–1281CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Maioli S, Bavner A, Ali Z, et al (2013). Is it possible to improve memory function by upregulation of the cholesterol 24S-hydroxylase (CYP46A1) in the brain? PLoS One 8: e68534-e68534CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Augustin I, Rosenmund C, Sudhof TC, et al (1999). Munc13-1 is essential for fusion competence of glutamatergic synaptic vesicles. Nature 400: 457–461CrossRefPubMedGoogle Scholar
  45. 45.
    Betz A, Thakur P, Junge HJ, et al (2001). Functional interaction of the active zone proteins Munc13-1 and RIM1 in synaptic vesicle priming. Neuron 30: 183–196CrossRefPubMedGoogle Scholar
  46. 46.
    Kornau HC, Schenker LT, Kennedy MB, et al (1995). Domain interaction between NMDA receptor subunits and the postsynaptic density protein PSD-95. Science 269: 1737–1740CrossRefPubMedGoogle Scholar
  47. 47.
    Choii G, Ko J (2015). Gephyrin: a central GABAergic synapse organizer. Exp Mol Med 47: e158CrossRefPubMedGoogle Scholar
  48. 48.
    Kwon SE, Chapman ER (2011). Synaptophysin regulates the kinetics of synaptic vesicle endocytosis in central neurons. Neuron 70: 847–854CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Kook SY, Jeong H, Kang MJ, et al (2014). Crucial role of calbindin-D28k in the pathogenesis of Alzheimer's disease mouse model. Cell Death Differ 21: 1575–1587CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Pickel VM, Heras A (1996). Ultrastructural localization of calbindin-D28k and GABA in the matrix compartment of the rat caudate-putamen nuclei. Neuroscience 71: 167–178CrossRefPubMedGoogle Scholar
  51. 51.
    Denker A, Bethani I, Krohnert K, et al (2011). A small pool of vesicles maintains synaptic activity in vivo. Proc Natl Acad Sci U S A 108: 17177–17182CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Gitler D, Takagishi Y, Feng J, et al (2004). Different presynaptic roles of synapsins at excitatory and inhibitory synapses. J Neurosci 24: 11368–11380CrossRefPubMedGoogle Scholar
  53. 53.
    Shupliakov O, Haucke V, Pechstein A (2011). How synapsin I may cluster synaptic vesicles. Semin Cell Dev Biol 22: 393–399CrossRefPubMedGoogle Scholar
  54. 54.
    Pekny M, Pekna M, Messing A, et al (2016). Astrocytes: a central element in neurological diseases. Acta Neuropathol 131: 323–345CrossRefGoogle Scholar
  55. 55.
    Mackenzie IR, Hao C, Munoz DG (1995). Role of microglia in senile plaque formation. Neurobiol Aging 16: 797–804CrossRefPubMedGoogle Scholar
  56. 56.
    Akiyama H, Mori H, Saido T, et al (1999). Occurrence of the diffuse amyloid beta-protein (Abeta) deposits with numerous Abeta-containing glial cells in the cerebral cortex of patients with Alzheimer's disease. Glia 25: 324–331CrossRefPubMedGoogle Scholar
  57. 57.
    Nagele RG, Wegiel J, Venkataraman V, et al (2004). Contribution of glial cells to the development of amyloid plaques in Alzheimer's disease. Neurobiol Aging 25: 663–674CrossRefPubMedGoogle Scholar
  58. 58.
    Ferrera D, Mazzaro N, Canale C, et al (2014). Resting microglia react to Abeta42 fibrils but do not detect oligomers or oligomer-induced neuronal damage. Neurobiol Aging 35: 2444–2457CrossRefPubMedGoogle Scholar
  59. 59.
    Hanzel CE, Pichet-Binette A, Pimentel LS, et al (2014). Neuronal driven pre-plaque inflammation in a transgenic rat model of Alzheimer's disease. Neurobiol Aging 35: 2249–2262CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Malm TM, Jay TR, Landreth GE (2015). The evolving biology of microglia in Alzheimer's disease. Neurotherapeutics 12: 81–93CrossRefPubMedGoogle Scholar
  61. 61.
    Piirainen S, Youssef A, Song C, et al (2017). Psychosocial stress on neuroinflammation and cognitive dysfunctions in Alzheimer's disease: the emerging role for microglia? Neurosci Biobehav Rev 77: 148–164CrossRefPubMedGoogle Scholar
  62. 62.
    Xing C, Li W, Deng W, et al (2018). A potential gliovascular mechanism for microglial activation: differential phenotypic switching of microglia by endothelium versus astrocytes. J Neuroinflammation 15: 143CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Shinozaki Y, Shibata K, Yoshida K, et al (2017). Transformation of Astrocytes to a Neuroprotective Phenotype by Microglia via P2Y1 Receptor Downregulation. Cell Rep 19: 1151–1164CrossRefPubMedGoogle Scholar
  64. 64.
    Ohyama Y, Meaney S, Heverin M, et al (2006). Studies on the transcriptional regulation of cholesterol 24-hydroxylase (CYP46A1): marked insensitivity toward different regulatory axes. J Biol Chem 281: 3810–3820CrossRefPubMedGoogle Scholar
  65. 65.
    Lu F, Zhu J, Guo S, et al (2018). Upregulation of cholesterol 24-hydroxylase following hypoxia-ischemia in neonatal mouse brain. Pediatr Res 83: 1218–1227CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Smiljanic K, Lavrnja I, Mladenovic Djordjevic A, et al (2010). Brain injury induces cholesterol 24-hydroxylase (Cyp46) expression in glial cells in a time-dependent manner. Histochem Cell Biol 134: 159–169CrossRefPubMedGoogle Scholar
  67. 67.
    Khatri N, Thankur M, Pareek V, et al (2018). Oxidative stress: Major threat in traumatic brain injury. CNS Neurol Disord Drug Targets 17: 689-695Google Scholar
  68. 68.
    Thornton C, Baburamani AA, Kichev A, et al (2017). Oxidative stress and endoplasmic reticulum (ER) stress in the development of neonatal hypoxic-ischaemic brain injury. Biochem Soc Trans 45: 1067–1076CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Linsenbardt AJ, Taylor A, Emnett CM, et al (2014). Different oxysterols have opposing actions at N-methyl-D-aspartate receptors. Neuropharmacology 85: 232–242CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Sun MY, Linsenbardt AJ, Emnett CM, et al (2016). 24(S)-Hydroxycholesterol as a modulator of neuronal signaling and survival. Neuroscientist 22: 132–144CrossRefPubMedGoogle Scholar
  71. 71.
    Abraham WC, Williams JM (2008). LTP maintenance and its protein synthesis-dependence. Neurobiol Learn Mem 89: 260–268CrossRefPubMedGoogle Scholar
  72. 72.
    Hoeffer CA, Klann E 2009 NMDA Receptors and Translational Control. In Biology of the NMDA Receptor. A. M. Van Dongen, editor. CRC Press/Taylor & Francis. Taylor & Francis Group, LLC., Boca Raton (FL), 103-121Google Scholar
  73. 73.
    Bramham CR (2008). Local protein synthesis, actin dynamics, and LTP consolidation. Curr Opin Neurobiol 18: 524–531CrossRefPubMedGoogle Scholar
  74. 74.
    Janowski BA, Willy PJ, Devi TR, et al (1996). An oxysterol signalling pathway mediated by the nuclear receptor LXR alpha. Nature 383: 728–731CrossRefPubMedGoogle Scholar
  75. 75.
    Kotti TJ, Ramirez DM, Pfeiffer BE, et al (2006). Brain cholesterol turnover required for geranylgeraniol production and learning in mice. Proc Natl Acad Sci U S A 103: 3869–3874CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Kotti T, Head DD, McKenna CE, et al (2008). Biphasic requirement for geranylgeraniol in hippocampal long-term potentiation. Proc Natl Acad Sci U S A 105: 11394–11399CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Moutinho M, Nunes MJ, Gomes AQ, et al (2015). Cholesterol 24S-Hydroxylase Overexpression Inhibits the Liver X Receptor (LXR) Pathway by Activating Small Guanosine Triphosphate-Binding Proteins (sGTPases) in Neuronal Cells. Mol Neurobiol 51: 1489–1503CrossRefPubMedGoogle Scholar
  78. 78.
    Allen NJ, Eroglu C (2017). Cell Biology of Astrocyte-Synapse Interactions. Neuron 96: 697–708CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Wu Y, Dissing-Olesen L, MacVicar BA, et al (2015). Microglia: Dynamic Mediators of Synapse Development and Plasticity. Trends Immunol 36: 605–613CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    Koffie RM, Meyer-Luehmann M, Hashimoto T, et al (2009). Oligomeric amyloid beta associates with postsynaptic densities and correlates with excitatory synapse loss near senile plaques. Proc Natl Acad Sci USA 106: 4012–4017CrossRefPubMedGoogle Scholar
  81. 81.
    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: 1304–1311CrossRefPubMedPubMedCentralGoogle Scholar
  82. 82.
    Ovsepian SV, Blazquez-Llorca L, Freitag SV, et al (2017). Ambient Glutamate Promotes Paroxysmal Hyperactivity in Cortical Pyramidal Neurons at Amyloid Plaques via Presynaptic mGluR1 Receptors. Cereb Cortex 27: 4733–4749PubMedGoogle Scholar
  83. 83.
    Ovsepian SV, O'Leary VB, Zaborszky L, et al (2018). Amyloid Plaques of Alzheimer's Disease as Hotspots of Glutamatergic Activity. Neuroscientist: in pressGoogle Scholar
  84. 84.
    Varoqueaux F, Sigler A, Rhee JS, et al (2002). Total arrest of spontaneous and evoked synaptic transmission but normal synaptogenesis in the absence of Munc13-mediated vesicle priming. Proc Natl Acad Sci U S A 99: 9037–9042CrossRefPubMedPubMedCentralGoogle Scholar
  85. 85.
    Shao CY, Mirra SS, Sait HB, et al (2011). Postsynaptic degeneration as revealed by PSD-95 reduction occurs after advanced Abeta and tau pathology in transgenic mouse models of Alzheimer's disease. Acta Neuropathol 122: 285–292CrossRefPubMedPubMedCentralGoogle Scholar
  86. 86.
    Crouzin N, Baranger K, Cavalier M, et al (2013). Area-specific alterations of synaptic plasticity in the 5XFAD mouse model of Alzheimer's disease: dissociation between somatosensory cortex and hippocampus. PLoS One 8: e74667CrossRefPubMedPubMedCentralGoogle Scholar
  87. 87.
    Kimura R, Ohno M (2009). Impairments in remote memory stabilization precede hippocampal synaptic and cognitive failures in 5XFAD Alzheimer mouse model. Neurobiology of disease 33: 229–235CrossRefPubMedGoogle Scholar
  88. 88.
    Ovsepian SV, O'Leary VB, Zaborszky L, et al (2018). Synaptic vesicle cycle and amyloid beta: Biting the hand that feeds. Alzheimers Dement 14: 502–513CrossRefPubMedGoogle Scholar
  89. 89.
    Vorhees CV, Williams MT (2006). Morris water maze: procedures for assessing spatial and related forms of learning and memory. Nat Protoc 1: 848–858CrossRefPubMedPubMedCentralGoogle Scholar
  90. 90.
    Young SL, Bohenek DL, Fanselow MS (1994). NMDA processes mediate anterograde amnesia of contextual fear conditioning induced by hippocampal damage: immunization against amnesia by context preexposure. Behav Neurosci 108: 19–29CrossRefPubMedGoogle Scholar
  91. 91.
    Sarnyai Z, Sibille EL, Pavlides C, et al (2000). Impaired hippocampal-dependent learning and functional abnormalities in the hippocampus in mice lacking serotonin(1A) receptors. Proc Natl Acad Sci U S A 97: 14731–14736CrossRefPubMedPubMedCentralGoogle Scholar
  92. 92.
    Anagnostaras SG, Wood SC, Shuman T, et al (2010). Automated assessment of pavlovian conditioned freezing and shock reactivity in mice using the video freeze system. Front Behav Neurosci 4: 158CrossRefPubMedPubMedCentralGoogle Scholar
  93. 93.
    Maruszak A, Thuret S (2014). Why looking at the whole hippocampus is not enough-a critical role for anteroposterior axis, subfield and activation analyses to enhance predictive value of hippocampal changes for Alzheimer's disease diagnosis. Front Cell Neurosci 8: 95–95CrossRefPubMedPubMedCentralGoogle Scholar
  94. 94.
    Nagahara AH, Merrill DA, Coppola G, et al (2009). Neuroprotective effects of brain-derived neurotrophic factor in rodent and primate models of Alzheimer's disease. Nat Med 15: 331–337CrossRefPubMedPubMedCentralGoogle Scholar
  95. 95.
    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: 1624–1634CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© The American Society for Experimental NeuroTherapeutics, Inc. 2019

Authors and Affiliations

  1. 1.Department of Ophthalmology and Visual SciencesCase Western Reserve UniversityClevelandUSA

Personalised recommendations