Skip to main content

Advertisement

SpringerLink
Log in

Evidence for Alzheimer’s disease-linked synapse loss and compensation in mouse and human hippocampal CA1 pyramidal neurons

  • Original Article
  • Published:
Brain Structure and Function Aims and scope Submit manuscript

Abstract

Alzheimer’s disease (AD) is associated with alterations in the distribution, number, and size of inputs to hippocampal neurons. Some of these changes are thought to be neurodegenerative, whereas others are conceptualized as compensatory, plasticity-like responses, wherein the remaining inputs reactively innervate vulnerable dendritic regions. Here, we provide evidence that the axospinous synapses of human AD cases and mice harboring AD-linked genetic mutations (the 5XFAD line) exhibit both, in the form of synapse loss and compensatory changes in the synapses that remain. Using array tomography, quantitative conventional electron microscopy, immunogold electron microscopy for AMPARs, and whole-cell patch-clamp physiology, we find that hippocampal CA1 pyramidal neurons in transgenic mice are host to an age-related synapse loss in their distal dendrites, and that the remaining synapses express more AMPA-type glutamate receptors. Moreover, the number of axonal boutons that synapse with multiple spines is significantly reduced in the transgenic mice. Through serial section electron microscopic analyses of human hippocampal tissue, we further show that putative compensatory changes in synapse strength are also detectable in axospinous synapses of proximal and distal dendrites in human AD cases, and that their multiple synapse boutons may be more powerful than those in non-cognitively impaired human cases. Such findings are consistent with the notion that the pathophysiology of AD is a multivariate product of both neurodegenerative and neuroplastic processes, which may produce adaptive and/or maladaptive responses in hippocampal synaptic strength and plasticity.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

References

  • Amaral D, Lavenex P (2007) Hippocampal neuroanatomy. In: Andersen P, Morris R, Amaral D, Bliss T, O’Keefe J (eds) The hippocampus book. Oxford UP, New York, pp 37–114

    Google Scholar 

  • Amiry-Moghaddam M, Ottersen OP (2013) Immunogold cytochemistry in neuroscience. Nat Neurosci 16:798–804

    Article  CAS  PubMed  Google Scholar 

  • Apostolova LG, Mosconi L, Thompson PM, Green AE, Hwang KS, Ramirez A, Mistur R, Tsui WH, de Leon MJ (2010) Subregional hippocampal atrophy predicts Alzheimer’s dementia in the cognitively normal. Neurobiol Aging 31:1077–1088

    Article  PubMed Central  PubMed  Google Scholar 

  • Ashe KH, Zahs KR (2010) Probing the biology of Alzheimer’s disease in mice. Neuron 66:631–645

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Berchtold NC, Coleman PD, Cribbs DH, Rogers J, Gillen DL, Cotman CW (2013) Synaptic genes are extensively downregulated across multiple brain regions in normal human aging and Alzheimer’s disease. Neurobiol Aging 34:1653–1661

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Bloss EB, Janssen WG, Ohm DT, Yuk FJ, Wadsworth S, Saardi KM, McEwen BS, Morrison JH (2011) Evidence for reduced experience-dependent dendritic spine plasticity in the aging prefrontal cortex. J Neurosci 31:7831–7839

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Bloss EB, Puri R, Yuk F, Punsoni M, Hara Y, Janssen WG, McEwen BS, Morrison JH (2013) Morphological and molecular changes in aging rat prelimbic prefrontal cortical synapses. Neurobiol Aging 34:200–210

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Born HA, Kim JY, Savjani RR, Das P, Dabaghian YA, Guo Q, Yoo JW, Schuler DR, Cirrito JR, Zheng H, Golde TE, Noebels JL, Jankowsky JL (2014) Genetic suppression of transgenic APP rescues hypersynchronous network activity in a mouse model of Alzheimer’s disease. J Neurosci 34:3826–3840

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Bourne J, Harris KM (2007) Do thin spines learn to be mushroom spines that remember? Curr Opin Neurobiol 17:381–386

    Article  CAS  PubMed  Google Scholar 

  • Buell SJ, Coleman PD (1979) Dendritic growth in the aged human brain and failure of growth in senile dementia. Science 206:854–856

    Article  CAS  PubMed  Google Scholar 

  • Camandola S, Mattson MP (2011) Aberrant subcellular neuronal calcium regulation in aging and Alzheimer’s disease. Biochim Biophys Acta 1813:965–973

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Chang EH, Savage MJ, Flood DG, Thomas JM, Levy RB, Mahadomrongkul V, Shirao T, Aoki C, Huerta PT (2006) AMPA receptor downscaling at the onset of Alzheimer’s disease pathology in double knockin mice. Proc Natl Acad Sci USA 103:3410–3415

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Cooper-Knock J, Kirby J, Ferraiuolo L, Heath PR, Rattray M, Shaw PJ (2012) Gene expression profiling in human neurodegenerative disease. Nat Rev Neurol 8:518–530

    Article  CAS  PubMed  Google Scholar 

  • Counts SE, Alldred MJ, Che S, Ginsberg SD, Mufson EJ (2014) Synaptic gene dysregulation within hippocampal CA1 pyramidal neurons in mild cognitive impairment. Neuropharmacology 79:172–179

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Crouzin N, Baranger K, Cavalier M, Marchalant Y, Cohen-Solal C, Roman FS, Khrestchatisky M, Rivera S, Feron F, Vignes M (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:e74667

  • De Jager PL, Bennett DA (2013) An inflection point in gene discovery efforts for neurodegenerative diseases: from syndromic diagnoses toward endophenotypes and the epigenome. JAMA Neurol 70:719–726

    Article  PubMed Central  PubMed  Google Scholar 

  • Dong H, Martin MV, Chambers S, Csernansky JG (2007) Spatial relationship between synapse loss and beta-amyloid deposition in Tg2576 mice. J Comp Neurol 500:311–321

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Dougherty KA, Islam T, Johnston D (2012) Intrinsic excitability of CA1 pyramidal neurones from the rat dorsal and ventral hippocampus. J Physiol 590:5707–5722

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Dougherty KA, Nicholson DA, Diaz L, Buss EW, Neuman KM, Chetkovich DM, Johnston D (2013) Differential expression of HCN subunits alters voltage-dependent gating of h-channels in CA1 pyramidal neurons from dorsal and ventral hippocampus. J Neurophysiol 109:1940–1953

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Dumitriu D, Hao J, Hara Y, Kaufmann J, Janssen WG, Lou W, Rapp PR, Morrison JH (2010) Selective changes in thin spine density and morphology in monkey prefrontal cortex correlate with aging-related cognitive impairment. J Neurosci 30:7507–7515

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Federmeier KD, Kleim JA, Greenough WT (2002) Learning-induced multiple synapse formation in rat cerebellar cortex. Neurosci Lett 332:180–184

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Fitzjohn SM, Morton RA, Kuenzi F, Rosahl TW, Shearman M, Lewis H, Smith D, Reynolds DS, Davies CH, Collingridge GL, Seabrook GR (2001) Age-related impairment of synaptic transmission but normal long-term potentiation in transgenic mice that overexpress the human APP695SWE mutant form of amyloid precursor protein. J Neurosci 21:4691–4698

    CAS  PubMed  Google Scholar 

  • Friedlander MJ, Martin KA, Wassenhove-McCarthy D (1991) Effects of monocular visual deprivation on geniculocortical innervations of area 18 in cat. J Neurosci 11:3268–3288

    CAS  PubMed  Google Scholar 

  • Funke L, Dakoji S, Bredt DS (2005) Membrane-associated guanylate kinases regulate adhesion and plasticity at cell junctions. Annu Rev Biochem 74:219–245

    Article  CAS  PubMed  Google Scholar 

  • Gaarskjaer FB (1978) Organization of the mossy fiber system of the rat studied in extended hippocampi. J Comp Neurol 178:49–72

    Article  CAS  PubMed  Google Scholar 

  • Ganeshina O, Berry RW, Petralia RS, Nicholson DA, Geinisman Y (2004) Differences in the expression of AMPA and NMDA receptors between axospinous perforated and nonperforated synapses are related to the configuration and size of postsynaptic densities. J Comp Neurol 468:86–95

    Article  CAS  PubMed  Google Scholar 

  • Geinisman Y, Gundersen HJ, van der Zee E, West MJ (1996) Unbiased stereological estimation of the total number of synapses in a brain region. J Neurocytol 25:805–819

    Article  CAS  PubMed  Google Scholar 

  • Geinisman Y, Berry RW, Disterhoft JF, Power JM, van der Zee EA (2001) Associative learning elicits the formation of multiple-synapse boutons. J Neurosci 21:5568–5573

    CAS  PubMed  Google Scholar 

  • Giannakopoulos P, Kövari E, Gold G, von Gunten A, Hof PR, Bouras C (2009) Pathological substrates of cognitive decline in Alzheimer’s disease. Front Neurol Neurosci 24:20–29

    Article  PubMed  Google Scholar 

  • Golding NL, Mickus TJ, Katz Y, Kath WL, Spruston N (2005) Factors mediating powerful voltage attenuation along CA1 pyramidal neuron dendrites. J Physiol 568:69–82

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Gomez-Isla T, Price JL, McKeel DW Jr, Morris JC, Growdon JH, Hyman BT (1996) Profound loss of layer II entorhinal cortex neurons occurs in very mild Alzheimer’s disease. J Neurosci 16:4491–4500

    CAS  PubMed  Google Scholar 

  • Grutzendler J, Helmin K, Tsai J, Gan WB (2007) Various dendritic abnormalities are associated with fibrillar amyloid deposits in Alzheimer’s disease. Ann NY Acad Sci 1097:30–39

    Article  PubMed  Google Scholar 

  • Hara Y, Park CS, Janssen WG, Punsoni M, Rapp PR, Morrison JH (2011) Synaptic characteristics of dentate gyrus axonal boutons and their relationships with aging, menopause, and memory in female rhesus monkeys. J Neurosci 31:7737–7744

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Harris KM (1995) How multiple-synapse boutons could preserve input specificity during an interneuronal spread of LTP. Trends Neurosci 18:365–369

  • Hatton GI (1990) Emerging concepts of structure-function dynamics in adult brain: the hypothalamo-neurohypophysial system. Prog Neurobiol 34:437–504

    Article  CAS  PubMed  Google Scholar 

  • Hsieh H, Boehm J, Sato C, Iwatsubo T, Tomita T, Sisodia S, Malinow R (2006) AMPAR removal underlies Abeta-induced synaptic depression and dendritic spine loss. Neuron 52:831–843

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Hyman BT, Yuan J (2012) Apoptotic and non-apoptotic roles of caspases in neuronal physiology and pathophysiology. Nat Rev Neurosci 13:395–406

    Article  CAS  PubMed  Google Scholar 

  • Hyman BT, Damasio H, Damasio AR, Van Hoesen GW (1989) Alzheimer’s disease. Annu Rev Public Health 10:115–140

    Article  CAS  PubMed  Google Scholar 

  • Jack CR Jr, Petersen RC, Xu YC, Waring SC, O’Brien PC, Tangalos EG, Smith GE, Ivnik RJ, Kokmen E (1997) Medial temporal atrophy on MRI in normal aging and very mild Alzheimer’s disease. Neurology 49:786–794

    Article  PubMed Central  PubMed  Google Scholar 

  • Jahn R, Fasshauer D (2012) Molecular machines governing exocytosis of synaptic vesicles. Nature 490:201–207

  • Jones TA (1999) Multiple synapse formation in motor cortex opposite unilateral sensorimotor cortex lesions in adult rats. J Comp Neurol 414:57–66

    Article  CAS  PubMed  Google Scholar 

  • Jones TA, Klintsova AY, Kilman VL, Sirevaag AM, Greenough WT (1997) Induction of multiple synapses by experience in the visual cortex of adult rats. Neurobiol Learn Mem 68:13–20

    Article  CAS  PubMed  Google Scholar 

  • Jones TA, Chu CJ, Grande LA, Gregory AD (1999) Motor skills training enhances lesion-induced structural plasticity in the motor cortex of adult rats. J Neurosci 19:10153–10163

    CAS  PubMed  Google Scholar 

  • Kamenetz F, Tomita T, Hsieh H, Seabrook G, Borchelt D, Iwatsubo T, Sisodia S, Malinow R (2003) APP processing and synaptic function. Neuron 37:925–937

    Article  CAS  PubMed  Google Scholar 

  • Kandalepas PC, Sadleir KR, Eimer WA, Zhao J, Nicholson DA, Vassar R (2013) The Alzheimer’s β-secretase BACE1 localizes to normal presynaptic terminals and to dystrophic presynaptic terminals surrounding amyloid plaques. Acta Neuropathol 126:329–352

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Kasai H, Hayama T, Ishikawa M, Watanabe S, Yagishita S, Noguchi J (2010) Learning rules and persistence of dendritic spines. Eur J Neurosci 32:241–249

    Article  PubMed  Google Scholar 

  • Kimura R, Ohno M (2009) Impairments in remote memory stabilization precede hippocampal synaptic and cognitive failures in 5XFAD Alzheimer mouse model. Neurobiol Dis 33:229–235

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Kimuro R, Devi L, Ohno M (2010) Partial reduction of BACE1 improves synaptic plasticity, recent and remote memories in Alzheimer’s disease transgenic mice. J Neurochem 113:248–261

    Article  CAS  Google Scholar 

  • Kirov SA, Sorra KE, Harris KM (1999) Slices have more synapses than perfusion-fixed hippocampus from both young and mature rats. J Neurosci 19:2876–2886

    CAS  PubMed  Google Scholar 

  • Kirov SA, Petrak LJ, Fiala JC, Harris KM (2004) Dendritic spines disappear with chilling but proliferate excessively upon rewarming of mature hippocampus. Neurosci 127:69–80

    Article  CAS  Google Scholar 

  • Koffie RM, Meyer-Luehman M, Hashimoto T, Adams KW, Mielke ML, Garcia-Alloza M, Micheva KD, Smith SJ, Kim ML, Lee VM, Hyman BT, Spires-Jones TL (2009) Oligomeric amyloid beta associates with postsynaptic densities and correlates with excitatory synapse loss near senile plaques. Proc Natl Acad Sci USA 106:4012–4017

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Koffie RM, Hyman BT, Spires-Jones TL (2011) Alzheimer’s disease: synapses gone cold. Mol Neurodegener 6:63

    Article  PubMed Central  PubMed  Google Scholar 

  • Kordower JH, Chu Y, Stebbins GT, DeKosky ST, Cochran EJ, Bennett D, Mufson EJ (2001) Loss and atrophy of layer II entorhinal cortex neurons in elderly people with mild cognitive impairment. Ann Neurol 49:202–213

    Article  CAS  PubMed  Google Scholar 

  • Lazarov O, Lee M, Peterson DA, Sisodia SS (2002) Evidence that synaptically released β-amyloid accumulates as extracellular deposits in the hippocampus of transgenic mice. J Neurosci 22:9785–9793

    CAS  PubMed  Google Scholar 

  • Magee JC, Cook EP (2000) Somatic EPSP amplitude is independent of synapse location in hippocampal pyramidal neurons. Nat Neurosci 3:895–903

    Article  CAS  PubMed  Google Scholar 

  • Malinow R (2012) New developments on the role of NMDA receptors in Alzheimer’s disease. Curr Opin Neurobiol 22:559–563

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM (1984) Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 34:939–944

    Article  CAS  PubMed  Google Scholar 

  • Medvedev NI, Dallérac G, Popov VI, Rodriguez Arellano JJ, Davies HA, Kraev IV, Doyère V, Stewart MG (2012) Multiple spine boutons are formed after long-lasting LTP in the awake rat. Brain Struct Funct. doi:10.1007/s00429-012-0488-0

    PubMed  Google Scholar 

  • Menon V, Musial TF, Liu A, Katz Y, Kath WL, Spruston N, Nicholson DA (2013) Balanced synaptic impact through distance-dependent synapse distribution and complementary expression of AMPA and NMDA receptors in hippocampal dendrites. Neuron 18:1451–1463

    Article  CAS  Google Scholar 

  • Merino-Serrais P, Knafo S, Alonso-Nanclares L, Fernaud-Espinosa I, DeFelipe J (2011) Layer-specific alterations to CA1 dendritic spines in a mouse model of Alzheimer’s disease. Hippocampus 21:1037–1044

    Article  CAS  PubMed  Google Scholar 

  • Meshul CK, Cogen JP, Cheng HW, Moore C, Krentz L, McNeill TH (2000) Alterations in rat striatal glutamate synapses following a lesion of the cortico- and/or nigrostriatal pathway. Exp Neurol 165:191–206

    Article  CAS  PubMed  Google Scholar 

  • Mesulam M, Shaw P, Mash D, Weintraub S (2004) Cholinergic nucleus basalis tauopathy emerges early in the aging-MCI-AD continuum. Ann Neurol 55:815–828

    Article  CAS  PubMed  Google Scholar 

  • Micheva KD, Smith SJ (2007) Array tomography: a new tool for imaging the molecular architecture and ultrastructure of neural circuits. Neuron 55:25–36

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Micheva KD, Busse B, Weiler NC, O’Rourke M, Smith SJ (2010) Single-synapse analysis of a diverse synapse population: proteomic imaging methods and markers. Neuron 68:639–653

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Morrison JH, Baxter MG (2012) The ageing cortical synapse: hallmarks and implications for cognitive decline. Nat Rev Neurosci 13:240–250

    PubMed Central  CAS  PubMed  Google Scholar 

  • Morrison JH, Baxter MG (2014) Synaptic health. JAMA Psychiatry. doi:10.1001/jamapsychiatry.2014.380

    PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Mucke L, Selkoe DJ (2012) Neurotoxicity of amyloid beta-protein: synaptic and network dysfunction. Cold Spring Harb Perspect Med 2:a006338

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Nicholson DA, Geinisman Y (2009) Axospinous synaptic subtype-specific differences in structure, size, ionotropic receptor expression, and connectivity in apical dendritic regions of rat hippocampal CA1 pyramidal neurons. J Comp Neurol 512:399–418

    Article  PubMed Central  PubMed  Google Scholar 

  • Nicholson DA, Trana R, Katz Y, Kath WL, Spruston N, Geinisman Y (2006) Distance-dependent differences in synapse number and AMPA receptor expression in hippocampal CA1 pyramidal neurons. Neuron 50:431–442

    Article  CAS  PubMed  Google Scholar 

  • Nixon RA (2013) The role of autophagy in neurodegenerative disease. Nat Med 19:983–997

    Article  CAS  PubMed  Google Scholar 

  • Oakley H, Cole SL, Logan S, Maus E, Shao P, Craft J, Guillozet-Bongaarts A, Ohno M, Disterhoft JF, Van Eldik L, Berry R, Vassar R (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 26:10129–10140

    Article  CAS  PubMed  Google Scholar 

  • Oddo S, Caccamo A, Shepherd JD, Murphy MP, Golde TE, Kayed R, Metherate R, Mattson MP, Akbari Y, LaFerla FM (2003) Triple-transgenic model of Alzheimer’s disease with plaques and tangles: intracellular Aβ and synaptic dysfunction. Neuron 39:409–421

    Article  CAS  PubMed  Google Scholar 

  • Oh K-J, Perez SE, Lagalwar S, Vana L, Binder L, Mufson EJ (2010) Staging of Alzheimer’s pathology in triple transgenic mice: a light and electron microscopic analysis. Int J Alzheimer’s Dis pii:780102

  • Ohno M (2009) Failures to reconsolidate memory in a mouse model of Alzheimer’s disease. Neurobiol Learn Mem 92:455–459

    Article  PubMed Central  PubMed  Google Scholar 

  • Ohno M, Sametsky EA, Younkin LH, Oakley H, Youngkin SG, Citron M, Vassar R, Disterhoft JF (2004) BACE1 deficiency rescues memory deficits and cholinergic dysfunction in a mouse model of Alzheimer’s disease. Neuron 41:27–33

    Article  CAS  PubMed  Google Scholar 

  • Ohno M, Cole SL, Yasvoina M, Zhao J, Citron M, Berry R, Disterhoft JF, Vassar R (2007) BACE1 gene deletion prevents neuron loss and memory deficits in 5XFAD APP/PS1 transgenic mice. Neurobiol Dis 26:134–145

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Probst A, Basler V, Bron B, Ulrich J (1983) Neuritic plaques in senile dementia of Alzheimer type; a Golgi analysis in the hippocampal region. Brain Res 268:249–254

    Article  CAS  PubMed  Google Scholar 

  • Querferth HW, LaFerla FM (2010) Alzheimer’s disease. N Eng J Med 362:329–344

    Article  Google Scholar 

  • Rasband WS (1997–2012) ImageJ, U. S. National Institutes of Health, Bethesda, Maryland, USA, http://imagej.nih.gov/ij/

  • Reilly JE, Hanson HH, Fernández-Monreal M, Wearne SL, Hof PR, Phillips GR (2011) Characterization of MSB synapses in dissociated hippocampal culture with simultaneous pre- and postsynaptic live microscopy. PLoS One 6:e26478

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Reitz C, Brayne C, Mayeux R (2011) Epidemiology of Alzheimer’s disease. Nat Rev Neurol 7:137–152

    Article  PubMed Central  PubMed  Google Scholar 

  • Rekart JL, Quinn B, Mesulam MM, Routtenberg A (2004) Subfield-specific increase in brain growth protein in postmortem hippocampus of Alzheimer’s patients. Neuroscience 126:579–584

    Article  CAS  PubMed  Google Scholar 

  • Ricoy EM, Mao P, Manczak M, Reddy PH, Frerking ME (2011) A transgenic mouse model of Alzheimer’s disease has impaired synaptic gain but normal synaptic dynamics. Neurosci Lett 500:212–215

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Rodriguez JJ, Noristani HN, Verkhratsky A (2012) The serotonergic system in ageing and Alzheimer’s disease. Prog Neurobiol 99:15–41

    Article  CAS  PubMed  Google Scholar 

  • Scheff SW, Price DA (2006) Alzheimer’s disease-related alterations in synaptic density: neocortex and hippocampus. J Alzheimers Dis 9:101–115

    PubMed  Google Scholar 

  • Scheff SW, Price DA, Schmitt FA, Mufson EJ (2006) Hippocampal synaptic loss in early Alzheimer’s disease and mild cognitive impairment. Neurobiol Aging 27:1372–1384

    Article  CAS  PubMed  Google Scholar 

  • Scheff SW, Price DA, Schmitt FA, DeKosky ST, Mufson EJ (2007) Synaptic alterations in CA1 in mild Alzheimer’s disease and mild cognitive impairment. Neurology 68:1501–1508

    Article  CAS  PubMed  Google Scholar 

  • Scheibel AB, Tomiyasu U (1978) Dendritic sprouting in Alzheimer’s presenile dementia. Exp Neurol 60:1–8

    Article  CAS  PubMed  Google Scholar 

  • Scheibel ME, Lindsay RD, Tomiyasu U, Scheibel AB (1976) Progressive dendritic changes in the aging human limbic system. Exp Neurol 53:420–430

    Article  CAS  PubMed  Google Scholar 

  • Schindelin J, Arganda-Carreras I, Frise E, Kaynig V, Longair M, Pietzsch T, Preibisch S, Rueden C, Saalfeld S, Schmid B, Tinevez JY, White DJ, Hartenstein V, Eliceiri K, Tomancak P, Cardona A (2012) Fiji: an open-source platform for biological-image analysis. Nat Methods 9:676–682

    Article  CAS  PubMed  Google Scholar 

  • Selkoe DJ (2011) Resolving controversies on the path to Alzheimer’s therapeutics. Nat Med 17:1060–1065

    Article  CAS  PubMed  Google Scholar 

  • Serrano-Pozzo A, Frosch MP, Masliah E, Hyman BT (2011) Neuropathological alterations in Alzheimer’s disease. Cold Spring Harb Perspect Med 1:a006189

    Google Scholar 

  • Shao CY, Mirra SS, Sait HB, Sacktor TC, Sigurdsson EM (2011) Postsynaptic degeneration as revealed by PSD-95 reduction occurs after advanced Aβ and tau pathology in transgenic mouse models of Alzheimer's disease. Acta Neuropathol 122:285–292

  • Sheng JG, Price DL, Koliatsos VW (2002) Disruption of corticocortical connections ameliorates amyloid burden in terminal fields in a transgenic model of Aβ amyloidosis. J Neurosci 22:9794–9799

    CAS  PubMed  Google Scholar 

  • Small SA, Schobel SA, Buxton RB, Witter MP, Barnes CA (2011) A pathophysiological framework of hippocampal dysfunction in ageing and disease. Nat Rev Neurosci 12:585–601

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Sorra KE, Harris KM (1993) Occurrence and three-dimensional structure of multiple synapses between individual radiatum axons and their target pyramidal cells in hippocampal area CA1. J Neurosci 13:3736–3748

    CAS  PubMed  Google Scholar 

  • Sorra KE, Mishra A, Kirov SA, Harris KM (2006) Dense core vesicles resemble active-zone transport vesicles and are diminished following synaptogenesis in mature hippocampal slices. Neurosci 141:2097–2106

    Article  CAS  Google Scholar 

  • Sperling RA, Dickerson BC, Pihlajamaki M, Vannini P, LaViolette PS, Vitolo OV, Hedden T, Becker JA, Rentz DM, Selkoe DJ, Johnson KA (2010) Functional alterations in memory networks in early Alzheimer’s disease. Neuromolecular Med 12:27–43

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Spires TL, Meyer-Luehmann M, Stern EA, McLean PJ, Skoch J, Nguyen PT, Bacskai BJ, Hyman BT (2005) Dendritic spine abnormalities in amyloid precursor protein transgenic mice demonstrated by gene transfer and intravital multiphoton microscopy. J Neurosci 25:7278–7287

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Spires-Jones T, Knafo S (2012) Spines, plasticity, and cognition in Alzheimer’s model mice. Neural Plast 2012:319836

    PubMed Central  PubMed  Google Scholar 

  • Sterio DC (1984) The unbiased estimation of number and sizes of arbitrary particles using the disector. J Microsc 134:127–136

    Article  CAS  PubMed  Google Scholar 

  • Steward O, Vinsant SL, Davis L (1988) The process of reinnervation in the dentate gyrus of adult rats: an ultrastructural study of changes in presynaptic terminal as a result of sprouting. J Comp Neurol 267:203–210

    Article  CAS  PubMed  Google Scholar 

  • Südhof TC, Rizo J (2011) Synaptic vesicle exocytosis. Cold Spring Harb Perspect Biol 3:pii.a005637

  • Terry RD, Masliah E, Salmon DP, Butters N, DeTeresa R, Hill R, Hansen LA, Katzman R (1991) Physical basis of cognitive alterations in Alzheimer’s disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol 30:572–580

    Article  CAS  PubMed  Google Scholar 

  • Toni N, Buchs PA, Nikonenko I, Bron CR, Muller D (1999) LTP promotes formation of multiple spine synapses between a single axon terminal and a dendrite. Nature 402:421–425

    Article  CAS  PubMed  Google Scholar 

  • Toni N, Teng EM, Bushong EA, Aimone JB, Zhao C, Consiglio A, van Praag H, Martone ME, Ellisman M, Gage FH (2007) Synapse formation on neurons born in the adult hippocampus. Nat Neurosci 10:727–734

    Article  CAS  PubMed  Google Scholar 

  • Van Strien NM, Cappaert NL, Witter MP (2009) The anatomy of memory: an interactive overview of the parahippocampal-hippocampal network. Nat Rev Neurosci 10:272–282

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • West MJ, Kawas CH, Stewart WF, Rudow GL, Troncoso JC (2004) Hippocampal neurons in pre-clinical Alzheimer’s disease. Neurobiol Aging 25:1205–1212

    Article  CAS  PubMed  Google Scholar 

  • West MJ, Bach G, Søderman A, Jensen JL (2009) Synaptic contact number and size in stratum radiatum CA1 of APP/PS1DeltaE9 transgenic mice. Neurobiol Aging 30:1756–1776

    Article  CAS  PubMed  Google Scholar 

  • Williams SR, Stuart GJ (2003) Role of dendritic synapse location in the control of action potential output. Trends Neurosci 26:147–154

    Article  CAS  PubMed  Google Scholar 

  • Woolley CS, Wenzel HJ, Schwartzkroin PA (1996) Estradiol increases frequency of multiple synapse boutons in the hippocampal CA1 region of the adult female rat. J Comp Neurol 373:108–117

    Article  CAS  PubMed  Google Scholar 

  • Wu HY, Hudry E, Hashimoto T, Kuchibhotla K, Rozkalne A, Fan Z, Spires-Jones T, Xie H, Arbel-Ornath M, Grosskreutz CL, Bacskai BJ, Hyman BT (2010) Amyloid beta induces the morphological neurodegenerative triad of spine loss, dendritic simplification, and neuritic dystrophies through calcineurin activation. J Neurosci 30:2636–2649

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Yamada M, Wada Y, Tsukagoshi H, Otomo E, Hayakawa M (1988) A quantitative Golgi study of basal dendrites of hippocampal CA1 pyramidal cells in senile dementia of Alzheimer type. J Neurol Neurosurg Psychiatry 51:1088–1090

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Yankova M, Hart SA, Woolley CS (2001) Estrogen increases synaptic connectivity between single presynaptic inputs and multiple postsynaptic CA1 pyramidal cells: a serial electron-microscopic study. Proc Natl Acad Sci USA 98:3525–3530

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Zito K, Scheuss V, Knott G, Hill T, Svoboda K (2009) Rapid functional maturation of nascent dendritic spines. Neuron 61:247–258

    Article  PubMed Central  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by NIH Grants AG031574 and AG047073, the Charles and M.R. Shapiro Foundation, and the Schild Foundation to D.A.N, and NIH Grants AG014449 and AG043375 to E.J.M. The authors thank Brad Busse, Kristina Micheva, Stephen Smith, and Tara Spires-Jones for their generous advice and help with the array tomography experiments.

Conflict of interest

None.

Author information

Authors and Affiliations

  1. Department of Neurological Sciences, Rush University Medical Center, 1653 West Harrison Street, Chicago, IL, 60612, USA

    Krystina M. Neuman, Elizabeth Molina-Campos, Timothy F. Musial, Andrea L. Price, Kwang-Jin Oh, Malerie L. Wolke, Eric W. Buss, Elliott J. Mufson & Daniel A. Nicholson

  2. Sanders Brown Center on Aging, University of Kentucky, Lexington, KY, 40536, USA

    Stephen W. Scheff

Authors
  1. Krystina M. Neuman
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Elizabeth Molina-Campos
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Timothy F. Musial
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Andrea L. Price
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kwang-Jin Oh
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Malerie L. Wolke
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Eric W. Buss
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Stephen W. Scheff
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Elliott J. Mufson
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Daniel A. Nicholson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Daniel A. Nicholson.

Additional information

K. M. Neuman, E. Molina-Campos, and T. F. Musial have contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Neuman, K.M., Molina-Campos, E., Musial, T.F. et al. Evidence for Alzheimer’s disease-linked synapse loss and compensation in mouse and human hippocampal CA1 pyramidal neurons. Brain Struct Funct 220, 3143–3165 (2015). https://doi.org/10.1007/s00429-014-0848-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00429-014-0848-z

Keywords

Search

Navigation