Skip to main content

Advertisement

SpringerLink
Log in

Synaptic degeneration in Alzheimer’s disease

  • Review
  • Published:
Acta Neuropathologica Aims and scope Submit manuscript

Abstract

Synaptic loss is the major neurobiological substrate of cognitive dysfunction in Alzheimer’s disease (AD). Synaptic failure is an early event in the pathogenesis that is clearly detectable already in patients with mild cognitive impairment (MCI), a prodromal state of AD. It progresses during the course of AD and in most early stages involves mechanisms of compensation before reaching a stage of decompensated function. This dynamic process from an initially reversible functionally responsive stage of down-regulation of synaptic function to stages irreversibly associated with degeneration might be related to a disturbance of structural brain self-organization and involves morphoregulatory molecules such as the amyloid precursor protein. Further, recent evidence suggests a role for diffusible oligomers of amyloid β in synaptic dysfunction. To form synaptic connections and to continuously re-shape them in a process of ongoing structural adaptation, neurons must permanently withdraw from the cell cycle. Previously, we formulated the hypothesis that differentiated neurons after having withdrawn from the cell cycle are able to use molecular mechanisms primarily developed to control proliferation alternatively to control synaptic plasticity. The existence of these alternative effector pathways within neurons might put them at risk of erroneously converting signals derived from plastic synaptic changes into the program of cell cycle activation, which subsequently leads to cell death. The molecular mechanisms involved in cell cycle activation might, thus, link aberrant synaptic changes to cell death.

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

Similar content being viewed by others

References

  1. Aoki C, Mahadomrongkul V, Fujisawa S, Habersat R, Shirao T (2007) Chemical and morphological alterations of spines within the hippocampus and entorhinal cortex precede the onset of Alzheimer’s disease pathology in double knock-in mice. J Comp Neurol 505(4):352–362

    PubMed  Google Scholar 

  2. Araki W, Kitaguchi N, Tokushima Y, Ishii K, Aratake H, Shimohama S, Nakamura S, Kimura J (1991) Trophic effect of beta-amyloid precursor protein on cerebral cortical neurons in culture. Biochem Biophys Res Commun 181:265–271

    PubMed  CAS  Google Scholar 

  3. Aranchio O, Chao MV (2007) Neurotrophins, synaptic plasticity and dementia. Curr Opin Neurobiol 17:1–6

    Google Scholar 

  4. Arendt T (2001) Alzheimer’s disease as a disorder of mechanisms underlaying structural brain self-organization. Commentary. Neuroscience 102:723–765

    PubMed  CAS  Google Scholar 

  5. Arendt T (2003) Synaptic plasticity and cell cycle activation in neurons are alternative effector pathways. The Dr. Jekyll and Mr. Hyde theory of Alzheimer’s disease or The yin and yang of neuroplasticity. Progr Neurobiol 71:83–248

    Google Scholar 

  6. Arendt T (2008) Differentiation and de-differentiation—Neuronal cell cycle regulation during development and age-related neurodegenerative disorders. In: Lajtha A et al (eds) Handbook of Neurochemistry and Molecular Neurobiology. Springer, New York, pp 160–197

  7. Arendt T, Bigl V, Tennstedt A, Arendt A (1985) Neuronal loss in different parts of the nucleus basalis is related to neuritic plaque formation in cortical target areas in Alzheimer’s disease. Neuroscience 14:1–14

    PubMed  CAS  Google Scholar 

  8. Arendt T, Brückner MK (2007) Linking cell-cycle dysfunction in Alzheimer’s disease to a failure of synaptic plasticity. Biochim Biophys Acta 1772(4):413–421

    PubMed  CAS  Google Scholar 

  9. Arendt T, Gärtner U, Seeger G, Barmashenko G, Palm K, Mittmann T, Yan L, Hümmeke M, Behrbohm J, Brückner MK, Holzer M, Wahle P, Heumann R (2004) Neuronal activation of Ras regulates synaptic connectivity. Eur J Neurosci 19:2953–2966

    PubMed  Google Scholar 

  10. Arendt T, Holzer M, Großmann A, Zedlick D, Brückner MK (1995) Increased expression and subcellular translocation of the mitogen-activated protein kinase kinase and mitogen-activated protein kinase in Alzheimer’s disease. Neuroscience 68:5–18

    PubMed  CAS  Google Scholar 

  11. Arendt T, Stieler J, Strijkstra AM, Hut RA, Rüdiger J, Van der Zee EA, Harkany T, Holzer M, Härtig W (2003) Reversible PHF-like phosphorylation of tau is an adaptive process associated with neuronal plasticity in hibernating animals. J Neurosci 18:6972–6981

    Google Scholar 

  12. Arendt T, Rödel L, Gärtner U, Holzer M (1996) Expression of the cyclin-dependent kinase inhibitor p16 in Alzheimer’s disease. Neuroreport 7:3047–3049

    PubMed  CAS  Google Scholar 

  13. Bai F, Zhang Z, Watson DR, Yu H, Shi Y, Yuan Y, Zang Y, Zhu C, Qian Y (2008) Abnormal functional connectivity of hippocampus during episodic memory retrieval processing network in amnestic mild cognitive impairment. Biol Psychiatry. 2008 Nov 22. [Epub ahead of print]

  14. Bain A (1872) Mind and body. The theories of their relation. D. Appleton & Company, New York

    Google Scholar 

  15. Barnes CA (1994) Normal aging: regionally specific changes in hippocampal synaptic transmission. Trends Neurosci 17:13–18

    PubMed  CAS  Google Scholar 

  16. Bell KF, Bennett DA, Cuello AC (2007) Paradoxical upregulation of glutamatergic presynaptic boutons during mild cognitive impairment. J Neurosci 27:10810–10817

    PubMed  CAS  Google Scholar 

  17. Bell KF, Zheng L, Fahrenholz F, Cuello AC (2008) ADAM-10 over-expression increases cortical synaptogenesis. Neurobiol Aging 29:554–565

    PubMed  CAS  Google Scholar 

  18. Bertoni-Freddari C, Fattoretti P, Casoli T, Meier-Ruge W, Ulrich J (1990) Morphological adaptive response of the synaptic junctional zones in the human dentate gyrus during aging and Alzheimer’s disease. Brain Res 517:69–75

    PubMed  CAS  Google Scholar 

  19. Bertoni-Freddari C, Fattoretti P, Meier-Ruge W, Ulrich J (1989) Computer-assisted morphometry of synaptic plasticity during aging and dementia. Pathol Res Pract 185:799–802

    PubMed  CAS  Google Scholar 

  20. Bertoni-Freddari C, Meier-Ruge W, Ulrich J (1988) Quantitative morphology of synaptic plasticity in the aging brain. Scanning Microsc 2:1027–1034

    PubMed  CAS  Google Scholar 

  21. Binnington JC, Kalisch BE (2007) Nitric oxide synthase inhibitors modulate nerve growth factor-mediated regulation of amyloid precursor protein expression in PC12 cells. J Neurochem 101:422–433

    PubMed  CAS  Google Scholar 

  22. Blennow K, Bogdanovic N, Alafuzoff I, Ekman R, Davidsson P (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(5):603–618

    PubMed  CAS  Google Scholar 

  23. Boynton S, Tully T (1992) latheo, a new gene involved in associative learning and memory in Drosophila melanogaster, identified from P element mutagenesis. Genetics 131:655–672

    PubMed  CAS  Google Scholar 

  24. Braak H, Braak E (1991) Neuropathological staging of Alzheimer related changes. Acta Neuropathol 82:239–259

    PubMed  CAS  Google Scholar 

  25. Brown DF, Risser RC, Bigio EH, Tripp P, Stiegler A, Welch E, Eagan KP, Hladik CL, White CL 3rd (1998) Neocortical synapse density and Braak stage in the Lewy body variant of Alzheimer disease: a comparison with classic Alzheimer disease and normal aging. J Neuropathol Exp Neurol 57(10):955–960

    PubMed  CAS  Google Scholar 

  26. Brun A, Liu X, Erikson C (1995) Synapse loss and gliosis in the molecular layer of the cerebral cortex in Alzheimer’s disease and in frontal lobe degeneration. Neurodegeneration 4(2):171–177

    PubMed  CAS  Google Scholar 

  27. Brunelli MP, Kowall NW, Lee JM, McKee AC (1991) Synaptophysin immunoreactivity is depleted in cortical laminae with dense dystrophic neurites and neurofibrillary tangles. J Neuropathol Exp Neurol 50:315

    Google Scholar 

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

    PubMed  CAS  Google Scholar 

  29. Callahan LM, Vaules WA, Coleman PD (2002) Progressive reduction of synaptophysin message in single neurons in Alzheimer disease. J Neuropathol Exp Neurol 61(5):384–395

    PubMed  CAS  Google Scholar 

  30. Callahan LM, Vaules WA, Coleman PD (1999) Quantitative decrease in synaptophysin message expression and increase in cathepsin D message expression in Alzheimer disease neurons containing neurofibrillary tangles. J Neuropathol Exp Neurol 58(3):275–287

    PubMed  CAS  Google Scholar 

  31. Chang JW, Schumacher E, Coulter PM 2nd, Vinters HV, Watson JB (1997) Dendritic translocation of RC3/neurogranin mRNA in normal aging, Alzheimer disease and fronto-temporal dementia. J Neuropathol Exp Neurol 56:1105–1118

    PubMed  CAS  Google Scholar 

  32. Chapman PF, White GL, Jones MW, Cooper-Blacketer D, Marshall VJ, Irizarry M, Younkin L, Good MA, Bliss TV, Hyman BT, Younkin SG, Hsiao KK (1999) Impaired synaptic plasticity and learning in aged amyloid precursor protein transgenic mice. Nat Neurosci 2:271–276

    PubMed  CAS  Google Scholar 

  33. Clinton J, Blackman SE, Royston MC, Roberts GW (1994) Differential synaptic loss in the cortex in Alzheimer’s disease: a study using archival material. Neuroreport 12; 5(4):497–500

    Google Scholar 

  34. Coleman PD, Yao PJ (2003) Synaptic slaughter in Alzheimer’s disease. Neurobiol Aging 24:1023–1027

    PubMed  CAS  Google Scholar 

  35. Cooke SF, Bliss TV (2006) Plasticity in the human central nervous system. Brain 129:1659–1673

    PubMed  CAS  Google Scholar 

  36. Counts SE, Nadeem M, Lad SP, Wuu J, Mufson EJ (2006) Differential expression of synaptic proteins in the frontal and temporal cortex of elderly subjects with mild cognitive impairment. J Neuropathol Exp Neurol 65(6):592–601

    PubMed  CAS  Google Scholar 

  37. Daigle I, Li C (1993) apl-1, a Caenorhabditis elegans gene encoding a protein related to the human beta-amyloid protein precursor. PNAS 90:12045–12049

    PubMed  CAS  Google Scholar 

  38. Davidsson P, Blennow K (1998) Neurochemical dissection of synaptic pathology in Alzheimer’s disease. Int Psychogeriatr 10(1):11–23

    PubMed  CAS  Google Scholar 

  39. Davidsson P, Jahn R, Bergquist J, Ekman R, Blennow K (1996) Synaptotagmin, a synaptic vesicle protein, is present in human cerebrospinal fluid: a new biochemical marker for synaptic pathology in Alzheimer disease? Mol Chem Neuropathol 27(2):195–210

    Article  PubMed  CAS  Google Scholar 

  40. 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

    PubMed  CAS  Google Scholar 

  41. Dawson GR, Seabrook GR, Zheng H, Smith DW, Graham S, O’Dowd G, Bowery BJ, Boyce S, Trumbauer ME, Chen HY, Van der Ploeg LH, Sirinathsinghji DJ (1999) Age-related cognitive deficits, impaired long-term potention and reduction in synaptic marker density in mice lacking the beta-amyloid precursor protein. Neurosci 90:1–13

    CAS  Google Scholar 

  42. DeKosky ST, Harbaugh RE, Schmitt FA, Bakay RA, Chui HC, Knopman DS, Reeder TM, Shetter AG, Senter HJ, Markesbery WR (1992) Cortical biopsy in Alzheimer’s disease: diagnostic accuracy and neurochemical, neuropathological, and cognitive correlations. Intraventricular Bethanecol Study Group. Ann Neurol 32(5):625–632

    PubMed  CAS  Google Scholar 

  43. DeKosky ST, Scheff SW, Styren SD (1996) Structural correlates of cognition in dementia: quantification and assessment of synapse change. Neurodegeneration 5(4):417–421 Review

    PubMed  CAS  Google Scholar 

  44. DeKosky ST, Scheff SW (1990) Synapse loss in frontal cortex biopsies in Alzheimer’s disease: correlation with cognitive severity. Ann Neurol 27(5):457–464

    PubMed  CAS  Google Scholar 

  45. Demoor J (1896) La plasticité morphologique des neurones cérébraux. Archives de Biologie 14:723–749

    Google Scholar 

  46. Dessi F, Colle MA, Hauw JJ, Duyckaerts C (1997) Accumulation of SNAP-25 immunoreactive material in axons of Alzheimer’s disease. Neuroreport 8:3685–3689

    PubMed  CAS  Google Scholar 

  47. Dickson DW, Crystal HA, Bevona C, Honer W, Vincent I, Davies P (1995) Correlations of synaptic and pathological markers with cognition of the elderly. Neurobiol Aging 16(3):285–298 discussion 298-304

    PubMed  CAS  Google Scholar 

  48. Dinamarca MC, Colombres M, Cerpa W, Bonansco C, Inestrosa NC (2008) Beta-amyloid oligomers affect the structure and function of the postsynaptic region: role of the Wnt signaling pathway. Neurodegener Dis 5:149–152

    PubMed  CAS  Google Scholar 

  49. Duval M (1895) Hypothèses sur la physiologie des centres nerveux; théorie histologique du sommeil. Comptes Rendus Hebdomadaires des Séances et Mémoires de la Société de Biologie 47:74–77

    Google Scholar 

  50. Duval M (1900) Les neurones. L’amiboïsme nerveux la théorie histologique du sommeil. Revue de l’Ècole d’Anthropologie de Paris 10:37–71

    Google Scholar 

  51. Espinosa B, Zenteno R, Mena R, Robitaille Y, Zenteno E, Guevara J (2001) O-Glycosylation in sprouting neurons in Alzheimer disease, indicating reactive plasticity. J Neuropathol Exp Neurol 60:441–448

    PubMed  CAS  Google Scholar 

  52. Featherstone DE, Broadie K (2000) Surprises from Drosophila: genetic mechanisms of synaptic development and plasticity. Brain Res Bull 53(5):501–511

    PubMed  CAS  Google Scholar 

  53. Fernandes MA, Proenca MT, Nogueira AJ, Oliveira LM, Santiago B, Santana I, Oliveira CR (1999) Effects of apolipoprotein E genotype on blood lipid composition and membrane platelet fluidity in Alzheimer’s disease. Biochem Biophys Acta 1454:89–96

    PubMed  CAS  Google Scholar 

  54. 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

    PubMed  CAS  Google Scholar 

  55. Flood DG, Coleman PD (1986) Failed compensatory dendritic growth as a pathophysiological process in Alzheimer’s disease. Can J Neurol Sci 13(Suppl. 4):475–479

    PubMed  CAS  Google Scholar 

  56. Fukumoto H, Cheung BS, Hyman BT, Irizarry MC (2002) Beta-secretase protein and activity are increased in the neocortex in Alzheimer disease. Arch Neurol 59(9):1381–1389

    PubMed  Google Scholar 

  57. Furukawa K, Sopher BL, Rydel RE, Begley JG, Pham DG, Martin GM, Fox M, Mattson MP (1996) Increased activity-regulating and neuroprotective efficacy of alpha-secretase-derived secreted amyloid precursor protein conferred by a C-terminal heparin-binding domain. J Neurochem 67:1882–1896

    PubMed  CAS  Google Scholar 

  58. Gabriel A, Klussmann FW, Igelmund P (1998) Rapid temperature changes induce adenosine-mediated depression of synaptic transmission in hippocampal slices from rats (non-hibernators). Neuroscience 86:67–77

    PubMed  CAS  Google Scholar 

  59. Gabriel SM, Haroutunian V, Powchik P, Honer WG, Davidson M, Davies P, Davis KL (1997) Increased concentrations of presynaptic proteins in the cingulate cortex of subjects with schizophrenia. Arch Gen Psychiatry 54(6):559–66. Erratum in: Arch Gen Psychiatry 1997 54(10):912

    Google Scholar 

  60. Gärtner U, Holzer M, Arendt T (1999) Elevated expression of p21ras is an early event in Alzheimer’s disease and precedes neurofibrillary degeneration. Neuroscience 91:1–5

    PubMed  Google Scholar 

  61. Gärtner U, Holzer M, Heumann R, Arendt T (1995) Induction of p21ras in Alzheimer pathology. Neuroreport 6:1441–1444

    PubMed  Google Scholar 

  62. Giacchino J, Criado JR, Games D, Henriksen S (2000) In vivo synaptic transmission in young and aged amyloid precursor protein transgenic mice. Brain Res 876:185–190

    PubMed  CAS  Google Scholar 

  63. Gibson PH (1983) EM study of the numbers of cortical synapses in the brains of ageing people and people with Alzheimer-type dementia. Acta Neuropathol (Berl) 62:127–133

    CAS  Google Scholar 

  64. Goate A, Chartier-Harlin MC, Mullan M, Brown J, Crawford F, Fidani L, Giuffra L, Haynes A, Irving N, James L, Mant R, Newton P, Rooke K, Roques P, Tabot C, Williamson R, Rossor M, Hardy J (1991) Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease. Nature 349:704–706

    PubMed  CAS  Google Scholar 

  65. Götz J, Ittner LM, Kins S (2006) Do axonal defects in tau and amyloid precursor protein transgenic animals model axonopathy in Alzheimer’s disease? J Neurochem 98:993–1006

    PubMed  Google Scholar 

  66. Gonatas NK, Anderson W, Evangelista I (1967) The contribution of altered synapses in the senile plaque: an electron microscopic study in Alzheimer’s dementia. J Neuropathol. Exp Neurol 26:25–39

    PubMed  CAS  Google Scholar 

  67. Gottfries CG, Karlsson I, Svennerholm L (1996) Membrane components separate early-onset Alzheimer’s disease from senile dementia of the Alzheimer type. Int Psychogeriatr 8:365–372

    PubMed  CAS  Google Scholar 

  68. Gralle M, Ferreira ST (2007) Structure and functions of the human amyloid precursor protein: the whole is more than the sum of its parts. Progr Neurobiol 82:11–32

    CAS  Google Scholar 

  69. Gunawardena S, Goldstein LS (2001) Disruption of axonal transport and neuronal viability by amyloid precursor protein mutations in Drosophila. Neuron 32:389–401

    PubMed  CAS  Google Scholar 

  70. Haass C, Schlossmacher MG, Hung AY, Vigo-Pelfrey C, Mellon A, Ostaszewski BL, Lieberburg I, Koo EH, Schenk D, Teplow DB, Selkoe DJ (1992) Amyloid beta-peptide is produced by cultured cells during normal metabolism. Nature 359:322–325

    PubMed  CAS  Google Scholar 

  71. Haass C, Selkoe DJ (2007) Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer’s amyloid beta-peptide. Nat Rev Mol Cell Biol 8:101–112

    PubMed  CAS  Google Scholar 

  72. Hamos JE, DeGennaro LJ, Drachman DA (1989) Synaptic loss in Alzheimer’s disease and other dementias. Neurol 39:355–361

    CAS  Google Scholar 

  73. Hansen LA, Daniel SE, Wilcock GK, Love S (1998) Frontal cortical synaptophysin in Lewy body diseases: relation to Alzheimer’s disease and dementia. J Neurol Neurosurg Psychiatry 64:653–656

    PubMed  CAS  Google Scholar 

  74. Härtig W, Stieler J, Boerema AS, Wolf J, Schmidt U, Weißfuß J, Bullmann T, Strijkstra AM, Arendt T (2007) Hamster model of tau hyperphosphorylation: selective vulnerability of cholinergic forebrain neurons during hibernation—implications for Alzheimer’s disease. Eur J Neurosci 25:69–80

    PubMed  Google Scholar 

  75. Harigaya Y, Shoji M, Shirao T, Hirai S (1996) Disappearance of actin-binding protein, drebrin, from hippocampal synapses in Alzheimer’s disease. J Neurosci Res 43:87–92

    PubMed  CAS  Google Scholar 

  76. Hasselmo ME (1997) A computational model of the progression of Alzheimer’s disease. MD Comput 14:181–191

    PubMed  CAS  Google Scholar 

  77. Hatanpää K, Isaacs KR, Shirao T, Brady DR, Rapoport SI (1999) Loss of proteins regulating synaptic plasticity in normal aging of the human brain and in Alzheimer disease. J Neuropathol Exp Neurol 58:637–643

    PubMed  Google Scholar 

  78. Heber S, Herms J, Gajic V, Hainfellner J, Aguzzi A, Rülicke T, von Kretzschmar H, von Koch C, Sisodia S, Tremml P, Lipp HP, Wolfer DP, Müller U (2000) Mice with combined gene knock-outs reveal essential and partially redundant functions of amyloid precursor protein family members. J Neurosci 20:7951–7963

    PubMed  CAS  Google Scholar 

  79. Heffernan JM, Eastwood SL, Nagy Z, Sanders MW, McDonald B, Harrison PJ (1998) Temporal cortex synaptophysin mRNA is reduced in Alzheimer’s disease and is negatively correlated with the severity of dementia. Exp Neurol 150(2):235–239

    PubMed  CAS  Google Scholar 

  80. Heinonen O, Lehtovirta M, Soininen H, Helisalmi S, Mannermaa A, Sorvari H, Kosunen O, Paljärvi L, Ryynänen M, Riekkinen PJ Sr (1995) Alzheimer pathology of patients carrying apolipoprotein E epsilon 4 allele. Neurobiol Aging 16(4):505–513

    PubMed  CAS  Google Scholar 

  81. Heinonen O, Soininen H, Sorvari H, Kosunen O, Paljärvi L, Koivisto E, Riekkinen PJ Sr (1995) Loss of synaptophysin-like immunoreactivity in the hippocampal formation is an early phenomenon in Alzheimer’s disease. Neuroscience 64(2):375–384

    PubMed  CAS  Google Scholar 

  82. Herms J, Anliker B, Heber S, Ring S, Fuhrmann M, Kretzschmar H, Sisodia S, Müller U (2004) Cortical dysplasia resembling human type 2 lissencephaly in mice lacking all three APP family members. EMBO J 23:4106–4115

    PubMed  CAS  Google Scholar 

  83. Honer WG, Dickson DW, Gleeson J, Davies P (1992) Regional synaptic pathology in Alzheimer’s disease. Neurobiol Aging 13(3):375–382

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  85. Horn D, Levy N, Ruppin E (1996) Neuronal-based synaptic compensation: a computational study in Alzheimer’s disease. Neural Comput 8:1227–1243

    PubMed  CAS  Google Scholar 

  86. Horwitz B, Grady CL, Schlageter NL, Duara R, Rapoport SI (1987) Intercorrelations of regional cerebral glucose metabolic rates in Alzheimer’s disease. Brain Res 407:294–306

    PubMed  CAS  Google Scholar 

  87. Hu NW, Smith IM, Walsh DM, Rowan MJ (2008) Soluble amyloid-beta peptides potently disrupt hippocampal synaptic plasticity in the absence of cerebrovascular dysfunction in vivo. Brain 131:2414–2424

    PubMed  Google Scholar 

  88. Huang Z, Zang K, Reichardt LF (2005) The origin recognition core complex regulates dendrite and spine development in postmitotic neurons. J Cell Biol 170:527–535

    PubMed  CAS  Google Scholar 

  89. Huber G, Bailly Y, Martin JR, Mariani J, Brugg B (1997) Synaptic beta-amyloid precursor proteins increase with learning capacity in rats. Neurosci 80:313–320

    CAS  Google Scholar 

  90. Hut RA, de Wilde MC, Strijkstra AM, Van der Zee EA, Daan S (2001) Neuronal changes in the hippocampus and SCN of hibernating ground squirrels. Soc Neurosci Abstr 27:535.11

    Google Scholar 

  91. Ishida A, Furukawa K, Keller JN, Mattson MP (1997) Secreted form of beta-amyloid precursor protein shifts the frequency dependency for induction of LTD, and enhances LTP in hippocampal slices. Neuroreport 8:2133–2137

    PubMed  CAS  Google Scholar 

  92. Johnson SC, Schmitz TW, Moritz CH, Meyerand ME, Rowley HA, Alexander AL, Hansen KW, Gleason CE, Carlsson CM, Ries ML, Asthana S, Chen K, Reiman EM, Alexander GE (2006) Activation of brain regions vulnerable to Alzheimer’s disease: the effect of mild cognitive impairment. Neurobiol Aging 27:1604–1612

    PubMed  CAS  Google Scholar 

  93. Jorgensen OS, Balázs R (1993) Plastic neuronal changes in Alzheimer’s disease associated with activation of astrocytes and enhanced neurotrophic activity. In: Corain B, Iqbal K, Nicolini M, Winblad B, Wisniewski H, Zatta P (eds) Alzheimer’s disease: advances in clinical and basic research. Wiley, Chichester, pp 189–198

    Google Scholar 

  94. Katzman R (1986) Alzheimer’s disease. N Engl J Med 314:964–973

    PubMed  CAS  Google Scholar 

  95. Kaufmann WA, Barnas U, Humpel C, Nowakowski K, DeCol C, Gurka P, Ransmayr G, Hinterhuber H, Winkler H, Marksteiner J (1998) Synaptic loss reflected by secretoneurin-like immunoreactivity in the human hippocampus in Alzheimer’s disease. Eur J Neurosci 10(3):1084–1094

    PubMed  CAS  Google Scholar 

  96. Kavanau JL (1997) Memory, sleep and the evolution of mechanisms of synaptic efficacy maintenance. Neuroscience 79:7–44

    PubMed  CAS  Google Scholar 

  97. Kirazov E, Kirazov L, Bigl V, Schliebs R (2001) Ontogenetic changes in protein level of amyloid precursor protein (APP) in growth cones and synaptosomes from rat brain and prenatal expression pattern of APP mRNA isoforms in developing rat embryo. Int J Dev Neurosci 19:287–296

    PubMed  CAS  Google Scholar 

  98. Klyubin I, Walsh DM, Cullen WK, Fadeeva JV, Anwyl R, Selkoe DJ, Rowan MJ (2004) Soluble Arctic amyloid beta protein inhibits hippocampal long-term potentiation in vivo. Eur J Neurosci 19:2839–2846

    PubMed  Google Scholar 

  99. Klyubin I, Walsh DM, Lemere CA, Cullen WK, Shankar GM, Betts V, Spooner ET, Jiang L, Anwyl R, Selkoe DJ, Rowan MJ (2005) Amyloid beta protein immunotherapy neutralizes Abeta oligomers that disrupt synaptic plasticity in vivo. Nat Med 11:556–561

    PubMed  CAS  Google Scholar 

  100. Koffie RM, Meyer-Luehmann 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(10):4012–4017

    PubMed  CAS  Google Scholar 

  101. Koo EH, Sisodia SS, Archer DR, Martin LJ, Weidemann A, Beyreuther K, Fischer P, Masters CL, Price DL (1990) Precursor of amyloid protein in Alzheimer disease undergoes fast anterograde axonal transport. PNAS 87:1561–1565

    PubMed  CAS  Google Scholar 

  102. Korade Z, Kenworthy AK (2008) Lipid rafts, cholesterol, and the brain. Neuropharmacology 55(8):1265–1273

    PubMed  CAS  Google Scholar 

  103. Krilowicz BL, Glotzbach SF, Heller HC (1988) Neuronal activity during sleep and complete bouts of hibernation. Am J Physiol 255:R1008–R1019

    PubMed  CAS  Google Scholar 

  104. Lambert MP, Barlow AK, Chromy BA, Edwards C, Freed R, Liosatos M, Morgan TE, Rozovsky I, Trommer B, Viola KL, Wals P, Zhang C, Finch CE, Krafft GA, Klein WL (1998) Diffusible, nonfibrillar ligands derived from Abeta1–42 are potent central nervous system neurotoxins. Proc Natl Acad Sci USA 95:6448–6453

    PubMed  CAS  Google Scholar 

  105. Lassmann H, Fischer P, Jellinger K (1993) Synaptic pathology of Alzheimer’s disease. Ann N Y Acad Sci 695:59–64

    PubMed  CAS  Google Scholar 

  106. Lassmann H, Weiler R, Fischer P, Bancher C, Jellinger K, Floor E, Danielczyk W, Seitelberger F, Winkler H (1992) Synaptic pathology in Alzheimer’s disease: immunological data for markers of synaptic and large dense-core vesicles. Neuroscience 46:1–8

    PubMed  CAS  Google Scholar 

  107. Lechner T, Adlassnig C, Humpel C, Kaufmann WA, Maier H, Reinstadler-Kramer K, Hinterhölzl J, Mahata SK, Jellinger KA, Marksteiner J (2004) Chromogranin peptides in Alzheimer’s disease. Exp Gerontol 39(1):101–113

    PubMed  CAS  Google Scholar 

  108. Lépine MR (1895) Théorie mécanique de la paralysie hystérique, du somnambulisme, du sommeil naturel et de la distraction. Soc Biol 5:85–86

    Google Scholar 

  109. Leuba G, Savioz A, Vernay A, Carnal B, Kraftsik R, Tardif E, Riederer I, Riederer BM (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

    PubMed  CAS  Google Scholar 

  110. Lewis DA, Campbell MJ, Terry RD, Morrison JH (1987) Laminar and regional distributions of neurofibrillary tangles and neuritic plaques in Alzheimer’s disease: a quantitative study of visual and auditory cortices. J Neurosci 7:1799–1808

    PubMed  CAS  Google Scholar 

  111. Leyssen M, Ayaz D, Hébert SS, Reeve S, De Strooper B, Hassan BA (2005) Amyloid precursor protein promotes post-developmental neurite arborization in the Drosophila brain. EMBO J 24:2944–2955

    PubMed  CAS  Google Scholar 

  112. Lippa CF, Hamos JE, Pulaski-Salo D, DeGennaro LJ, Drachman DA (1992) Alzheimer’s disease and aging: effects on perforant pathway perikarya and synapses. Neurobiol Aging 13:405–411

    PubMed  CAS  Google Scholar 

  113. Liu X, Erikson C, Brun A (1996) Cortical synaptic changes and gliosis in normal aging, Alzheimer’s disease and frontal lobe degeneration. Dementia 7(3):128–134

    PubMed  CAS  Google Scholar 

  114. Löffler J, Huber G (1992) β-amyloid precirsor protein isoforms in various rat brain regions and during development. J. Neurochem 59:1316–1324

    PubMed  Google Scholar 

  115. López-Sánchez N, Müller U, Frade JM (2005) Lengthening of G2/mitosis in cortical precursors from mice lacking β-amyloid precursor protein. Neurosci 130:51–60

    Google Scholar 

  116. Lubec G, Nonaka M, Krapfenbauer K, Gratzer M, Cairns N, Fountoulakis M (1999) Expression of the dihydropyrimidinase related protein 2 (DRP-2) in Down syndrome and Alzheimer’s disease brain is downregulated at the mRNA and dysregulated at the protein level. J Neural Transm, Suppl. 57:161–177

    Google Scholar 

  117. Lue LF, Brachova L, Civin WH, Rogers J (1996) Inflammation, A beta deposition, and neurofibrillary tangle formation as correlates of Alzheimer’s disease neurodegeneration. J Neuropathol Exp Neurol 55(10):1083–1088

    PubMed  CAS  Google Scholar 

  118. Lugaro E (1895) Sulle Modificazioni delle cellule nervose. Lo Sperimentale 49:159–193

    Google Scholar 

  119. Lugaro E (1898) Sulle modificazioni morfologiche funzionali die dendriti delle cellule nervose. Rivista di Patologia Nervosa e Mentale 3:337–359

    Google Scholar 

  120. Lugaro E (1899) I recenti progressi dell’anatomia del sistema nervoso in rapporto alla psicologia ed alla psichiatria. Rivista di Patologia Nervosa e Mentale 4:481–514

    Google Scholar 

  121. Lugaro E (1900) I recenti progressi dell’anatomia del sistema nervoso in rapporto alla psicologia ed alla psichiatria. Rivista Sperimentale di Freniatria e Medicina Legale delle Alienazioni Mentali 26:831–894

    Google Scholar 

  122. Luo LQ, Martin-Morris LE, White K (1990) Identification, secretion, and neural expression of APPL, a Drosophila protein similar to human amyloid protein precursor. J Neurosci 10:3849–3861

    PubMed  CAS  Google Scholar 

  123. Ma H, Lesné S, Kotilinek L, Steidl-Nichols JV, Sherman M, Younkin L, Younkin S, Forster C, Sergeant N, Delacourte A, Vassar R, Citron M, Kofuji P, Boland LM, Ashe KH (2007) Involvement of beta-site APP cleaving enzyme 1 (BACE1) in amyloid precursor protein-mediated enhancement of memory and activity-dependent synaptic plasticity. PNAS 104:8167–8172

    PubMed  CAS  Google Scholar 

  124. Magara F, Müller U, Li ZW, Lipp HP, Weissmann C, Stagljar M, Wolfer DP (1999) Genetic background changes the pattern of forebrain commissure defects in transgenic mice underexpressing the beta-amyloid-precursor protein. PNAS 96:4656–4661

    PubMed  CAS  Google Scholar 

  125. Magariños AM, McEwen BS, Saboureau M, Pevet P (2006) Rapid and reversible changes in intrahippocampal connectivity during the course of hibernation in European hamsters. Proc Natl Acad Sci USA 103:18775–18780

    PubMed  Google Scholar 

  126. Majocha RE, Jungalwala FB, Rodenrys A, Marotta CA (1989) Monoclonal antibody to embryonic CNS antigen A2B5 provides evidence for the involvement of membrane components at sites of Alzheimer degeneration and detects sulfatides as well as gangliosides. J Neurochem 53:953–961

    PubMed  CAS  Google Scholar 

  127. Marksteiner J, Kaufmann WA, Gurka P, Humpel C (2002) Synaptic proteins in Alzheimer’s disease. J Mol Neurosci 18(1–2):53–63

    PubMed  CAS  Google Scholar 

  128. Marksteiner J, Lechner T, Kaufmann WA, Gurka P, Humpel C, Nowakowski C, Maier H, Jellinger KA (2000) Distribution of chromogranin B-like immunoreactivity in the human hippocampus and its changes in Alzheimer’s disease. Acta Neuropathol 100(2):205–212

    PubMed  CAS  Google Scholar 

  129. Martin-Morris LE, White K (1990) The Drosophila transcript encoded by the beta-amyloid protein precursor-like gene is restricted to the nervous system. Development 110:185–195

    PubMed  CAS  Google Scholar 

  130. Masliah E (1995) Mechanisms of synaptic dysfunction in Alzheimer’s disease. Histol Histopathol 10:509–519

    PubMed  CAS  Google Scholar 

  131. Masliah E, Alford M, DeTeresa R, Mallory M, Hansen L (1996) Deficient glutamate transport is associated with neurodegeneration in Alzheimer’s disease. Ann Neurol 40(5):759–766

    PubMed  CAS  Google Scholar 

  132. Masliah E, Ellisman M, Carragher B, Mallory M, Young S, Hansen L, DeTeresa R, Terry RD (1992) Three-dimensional analysis of the relationship between synaptic pathology and neuropil threads in Alzheimer disease. J Neuropathol Exp Neurol 51(4):404–414

    PubMed  CAS  Google Scholar 

  133. Masliah E, Mallory M, Alford M, DeTeresa R, Hansen LA, McKeel DW Jr, Morris JC (2001) Altered expression of synaptic proteins occurs early during progression of Alzheimer’s disease. Neurol 56:127–129

    CAS  Google Scholar 

  134. Masliah E, Mallory M, Ge N, Alford M, Veinbergs I, Roses AD (1995) Neurodegeneration in the central nervous system of apoE-deficient mice. Exp Neurol 136(2):107–122

    PubMed  CAS  Google Scholar 

  135. Masliah E, Mallory M, Hansen L, DeTeresa R, Alford M, Terry R (1994) Synaptic and neuritic alterations during the progression of Alzheimer’s disease. Neurosci Lett 174(1):67–72

    PubMed  CAS  Google Scholar 

  136. Masliah E, Mallory M, Hansen L, DeTeresa R, Terry RD (1993) Quantitative synaptic alterations in the human neocortex during normal aging. Neurology 43:192–197

    PubMed  CAS  Google Scholar 

  137. Masliah E, Terry R (1993) The role of synaptic proteins in the pathogenesis of disorders of the central nervous system. Brain Pathol 3(1):77–85

    PubMed  CAS  Google Scholar 

  138. Masliah E, Terry R (1994) The role of synaptic pathology in the mechanisms of dementia in Alzheimer’s disease. Clin Neurosci 1:192–198

    Google Scholar 

  139. Masliah E, Terry RD, Alford M, DeTeresa R, Hansen LA (1991) Cortical and subcortical patterns of synaptophysinlike immunoreactivity in Alzheimer’s disease. Am J Pathol 138(1):235–246

    PubMed  CAS  Google Scholar 

  140. Masliah E, Terry RD, DeTeresa RM, Hansen LA (1989) Immunohistochemical quantification of the synapse-related protein synaptophysin in Alzheimer disease. Neurosci Lett 103(2):234–239

    PubMed  CAS  Google Scholar 

  141. Masliah E, Terry RD, Mallory M, Alford M, Hansen LA (1990) Diffuse plaques do not accentuate synapse loss in Alzheimer’s disease. Am J Pathol 137(6):1293–1297

    PubMed  CAS  Google Scholar 

  142. Masters CL, Simms G, Weinman NA, Multhaup G, McDonald BL, Beyreuther K (1985) Amyloid plaque core protein in Alzheimer disease and Down syndrome. PNAS 82:4245–4249

    PubMed  CAS  Google Scholar 

  143. Mattson MP, Cheng B, Culwell AR, Esch FS, Lieberburg I, Rydel RE (1993) Evidence for excitoprotective and intraneuronal calcium-regulating roles for secreted forms of the beta-amyloid precursor protein. Neuron 10:243–254

    PubMed  CAS  Google Scholar 

  144. Mattson MP (1994) Secreted forms of beta-amyloid precursor protein modulate dendrite outgrowth and calcium responses to glutamate in cultured embryonic hippocampal neurons. J Neurobiol 25:439–450

    PubMed  CAS  Google Scholar 

  145. Meziane H, Dodart JC, Mathis C, Little S, Clemens J, Paul SM, Ungerer A (1998) Memory-enhancing effects of secreted forms of the beta-amyloid precursor protein in normal and amnestic mice. Proc Natl Acad Sci USA 95:12683–12688

    PubMed  CAS  Google Scholar 

  146. Mikkonen M, Soininen H, Tapiola T, Alafuzoff I, Miettinen R (1999) Hippocampal plasticity in Alzheimer’s disease: changes in highly polysialylated NCAM immunoreactivity in the hippocampal formation. Eur J Neurosci 11:1754–1764

    PubMed  CAS  Google Scholar 

  147. Millesi E, Prossinger H, Dittami JP, Fieder M (2001) Hibernation effects on memory in European ground squirrels (Spermophilus citellus). J Biol Rhythm 16:264–271

    CAS  Google Scholar 

  148. Milward EA, Papadopoulos R, Fuller SJ, Moir RD, Small D, Beyreuther K, Masters CL (1992) The amyloid protein precursor of Alzheimer’s disease is a mediator of the effects of nerve growth factor on neurite outgrowth. Neuron 9:129–137

    PubMed  CAS  Google Scholar 

  149. Minger SL, Honer WG, Esiri MM, McDonald B, Keene J, Nicoll JA, Carter J, Hope T, Francis PT (2001) Synaptic pathology in prefrontal cortex is present only with severe dementia in Alzheimer disease. J Neuropathol Exp Neurol 60(10):929–936

    PubMed  CAS  Google Scholar 

  150. Morrison JH, Hof PR, Campell MJ, DeLima AD, Voigt T, Bouras C, Cox K, Young WG (1990) Cellular pathology in Alzheimer’s disease: implications for corticocortical disconnection and differential vulnerability. In: Rapoport SI, Petit H, Leys D, Christen Y (eds) Imaging, Cerebral Topography and Alzheimer’s disease. Research and Perspectives in Alzheimer’s disease. Springer, Berlin, pp 19–40

    Google Scholar 

  151. Mucke L, Masliah E, Johnson WB, Ruppe MD, Alford M, Rockenstein EM, Forss-Petter S, Pietropaolo M, Mallory M, Abraham CR (1994) Synaptotrophic effects of human amyloid beta protein precursors in the cortex of transgenic mice. Brain Res 666:151–167

    PubMed  CAS  Google Scholar 

  152. Mucke L, Masliah E, Yu GQ, Mallory M, Rockenstein EM, Tatsuno G, Hu K, Kholodenko D, Johnson-Wood K, McConlogue L (2000) High-level neuronal expression of Aβ1–42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation. J Neurosci 20:4050–4058

    PubMed  CAS  Google Scholar 

  153. Mukaetova-Ladinska EB, Garcia-Siera F, Hurt J, Gertz HJ, Xuereb JH, Hills R, Brayne C, Huppert FA, Paykel ES, McGee M, Jakes R, Honer WG, Harrington CR, Wischik CM (2000) Staging of cytoskeletal and beta-amyloid changes in human isocortex reveals biphasic synaptic protein response during progression of Alzheimer’s disease. Am J Pathol 157(2):623–636

    PubMed  CAS  Google Scholar 

  154. Muntané G, Dalfó E, Martinez A, Ferrer I (2008) Phosphorylation of tau and alpha-synuclein in synaptic-enriched fractions of the frontal cortex in Alzheimer’s disease, and in Parkinson’s disease and related alpha-synucleinopathies. Neuroscience 152:913–923

    PubMed  Google Scholar 

  155. Nagy Z, Esiri MM, Smith AD (1997) Expression of cell division markers in the hippocampus in Alzheimer’s disease and other neurodegenerative conditions. Acta Neuropathol 93:294–300

    PubMed  CAS  Google Scholar 

  156. Origlia N, Righi M, Capsoni S, Cattaneo A, Fang F, Stern DM, Chen JX, Schmidt AM, Arancio O, Yan SD, Domenici L (2008) Receptor for advanced glycation end product-dependent activation of p38 mitogen-activated protein kinase contributes to amyloid-beta-mediated cortical synaptic dysfunction. J Neurosci 28:3521–3530

    PubMed  CAS  Google Scholar 

  157. Perdahl E, Adolfsson R, Alafuzoff I, Albert KA, Nestler EJ, Greengard P, Winblad B (1984) Synapsin I (protein I) in different brain regions in senile dementia of Alzheimer type and in multi-infarct dementia. J Neural Transm 60(2):133–141

    PubMed  CAS  Google Scholar 

  158. Perry EK, Tomlinson BE, Blessed G, Bergmann K, Gibson PH, Perry RH (1978) Correlation of cholinergic abnormalities with senile plaques and mental test scores in senile dementia. Br Med J 25;2(6150):1457–1459

    Google Scholar 

  159. Phinney AL, Calhoun ME, Wolfer DP, Lipp HP, Zheng H, Jucker M (1999) No hippocampal neuron or synaptic bouton loss in learning-impaired aged beta-amyloid precursor protein-null mice. Neurosci 90:1207–1216

    CAS  Google Scholar 

  160. Pinto S, Quintana DG, Smith P, Mihalek RM, Hou ZH, Boynton S, Jones CJ, Hendricks M, Velinzon K, Wohlschlegel JA, Austin RJ, Lane WS, Tully T, Dutta A (1999) latheo encodes a subunit of the origin recognition complex and disrupts neuronal proliferation and adult olfactory memory when mutant. Neuron 23:45–54

    PubMed  CAS  Google Scholar 

  161. Plant LD, Boyle JP, Smith IF, Peers C, Pearson HA (2003) The production of amyloid beta peptide is a critical requirement for the viability of central neurons. J Neurosci 23:5531–5535

    PubMed  CAS  Google Scholar 

  162. Popov VI, Bocharova LS (1992) Hibernation-induced structural changes in synaptic contracts between mossy fibres and hippocampal neurons. Neuroscience 48:53–62

    PubMed  CAS  Google Scholar 

  163. Popov VL, Bocharova LS, Bragin AG (1992) Repeated changes of dendritic morphology in the hippocampus of ground squirrels in the course of hibernation. Neuroscience 48:45–51

    PubMed  CAS  Google Scholar 

  164. Puzzo D, Privitera L, Leznik E, Fà M, Staniszewski A, Palmeri A, Arancio O (2008) Picomolar amyloid-beta positively modulates synaptic plasticity and memory in hippocampus. J Neurosci 28:14537–14545

    PubMed  CAS  Google Scholar 

  165. Rabl-Rückhard (1890) Sind die Ganglienzellen amöboid? Eine Hypothese zur Mechanik psychischer Vorgänge. Neurologisches Centralblatt 9:199–200

    Google Scholar 

  166. Ramón y Cajal S (1894) The Croonian lecture. La fine structure des centres nerveux. Proceedings of the Royal Society of London. vol. LV. Harrison and Sons, London, pp 444–468

    Google Scholar 

  167. Ramón y Cajal S (1911) Histologie du systeme nerveux. A. Maloine. Paris. (This is the second edition, in French, of the Textura del sistema nervioso del hombre y los vertebrados of 1899. Quotations here are from the English translation by N. and L. Swanson, vol 1. Oxford University Press 1995, New York

    Google Scholar 

  168. Ramón y Cajal S (1928) Degeneration and regeneration of the nervous system. Oxford University Press, London

    Google Scholar 

  169. Rapoport SI (1999) In vivo PET imaging and postmortem studies suggest potentially reversible and irreversible stages of brain metabolic failure in Alzheimer’s disease. Eur Arch Psychiatry Clin Neurosci 249(Suppl 3):46–55

    PubMed  Google Scholar 

  170. Reddy PH, Mani G, Park BS, Jacques J, Murdoch G, Whetsell W Jr, Kaye J, Manczak M (2005) Differential loss of synaptic proteins in Alzheimer’s disease: implications for synaptic dysfunction. J Alzheimers Dis 7:103–117

    PubMed  CAS  Google Scholar 

  171. Roch JM, Masliah E, Roch-Levecq AC, Sundsmo MP, Otero DA, Veinbergs I, Saitoh T (1994) Increase of synaptic density and memory retention by a peptide representing the trophic domain of the amyloid beta/A4 protein precursor. PNAS 91:7450–7454

    PubMed  CAS  Google Scholar 

  172. Rohrbough J, Pinto S, Mihalek RM, Tully T, Broadie K (1999) latheo, a Drosophila gene involved in learning, regulates functional synaptic plasticity. Neuron 23:55–70

    PubMed  CAS  Google Scholar 

  173. Rosen DR, Martin-Morris L, Luo LQ, White K (1989) A Drosophila gene encoding a protein resembling the human beta-amyloid protein precursor. PNAS 86:2478–2482

    PubMed  CAS  Google Scholar 

  174. Rossner S, Ueberham U, Schliebs R, Perez-Polo JR, Bigl V (1998) p75 and TrkA receptor signaling independently regulate amyloid precursor protein mRNA expression, isoform composition, and protein secretion in PC12 cells. J.Neurochem 71:757–766

    Article  PubMed  CAS  Google Scholar 

  175. Rossner S, Ueberham U, Schliebs R, Perez-Polo JR, Bigl V (1998) The regulation of amyloid precursor protein metabolism by cholinergic mechanisms and neurotrophin receptor signaling. Progr Neurobiol 56:541–569

    CAS  Google Scholar 

  176. Rowan MJ, Klyubin I, Wang Q, Hu NW, Anwyl R (2007) Synaptic memory mechanisms: Alzheimer’s disease amyloid beta-peptide-induced dysfunction. Biochem Soc Trans 35:1219–1223

    PubMed  CAS  Google Scholar 

  177. Ruiz-León Y, Pascual A (2004) Regulation of beta-amyloid precursor protein expression by brain-derived neurotrophic factor involves activation of both the Ras and phosphatidylinositide 3-kinase signalling pathways. J Neurochem 88:1010–1018

    PubMed  Google Scholar 

  178. Sabo SL, Ikin AF, Buxbaum JD, Greengard P (2003) The amyloid precursor protein and its regulatory protein, FE65, in growth cones and synapses in vitro and in vivo. J Neurosci 23:5407–5415

    PubMed  CAS  Google Scholar 

  179. Salbaum JM, Ruddle FH (1994) Embryonic expression pattern of amyloid protein precursor suggests a role in differentiation of specific subsets of neurons. J Exp Zool 269:116–127

    PubMed  CAS  Google Scholar 

  180. Samuel W, Alford M, Hofstetter CR, Hansen L (1997) Dementia with Lewy bodies versus pure Alzheimer disease: differences in cognition, neuropathology, cholinergic dysfunction, and synapse density. J Neuropathol Exp Neurol 56(5):499–508

    PubMed  CAS  Google Scholar 

  181. Samuel W, Terry RD, DeTeresa R, Butters N, Masliah E (1994) Clinical correlates of cortical and nucleus basalis pathology in Alzheimer dementia. Arch Neurol 51(8):772–778

    PubMed  CAS  Google Scholar 

  182. Scheff SW, DeKosky ST, Price DA (1990) Quantitative assessment of cortical synaptic density in Alzheimer’s disease. Neurobiol Aging 11(1):29–37

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  184. Scheff SW, Price DA, Schmitt FA, Mufson EJ (2006) Hippocampal synaptic loss in early Alzheimer’s disease and mild cognitive impairment. Neurobiol Aging 27(10):1372–1384

    PubMed  CAS  Google Scholar 

  185. Schmetsdorf S, Gärtner U, Arendt T (2005) Expression of cell cycle-related proteins in developing and adult mouse hippocampus. Int J Dev Neurosci 23:101–112

    PubMed  CAS  Google Scholar 

  186. Schmetsdorf S, Gärtner U, Arendt T (2007) Constitutive expression of functionally active cyclin-dependent kinases and their binding partners suggests noncanonical functions of cell cycle regulators in differentiated neurons. Cereb. Cortex 17(8):1821–1829

    PubMed  Google Scholar 

  187. Schubert W, Prior R, Weidemann A, Dircksen H, Multhaup G, Masters CL, Beyreuther K (1991) Localization of Alzheimer beta A4 amyloid precursor protein at central and peripheral synaptic sites. Brain Res 563:184–194

    PubMed  CAS  Google Scholar 

  188. Seabrook GR, Smith DW, Bowery BJ, Easter A, Reynolds T, Fitzjohn SM, Morton RA, Zheng H, Dawson GR, Sirinathsinghji DJ, Davies CH, Collingridge GL, Hill RG (1999) Mechanisms contributing to the deficits in hippocampal synaptic plasticity in mice lacking amyloid precursor protein. Neuropharmacology 38:349–359

    PubMed  CAS  Google Scholar 

  189. Seeger G, Gärtner U, Ueberham U, Rohn S, Arendt T (2009) FAD-mutation of APP is associated with a loss of its synaptotrophic activity. Neurobiology of Disease (under revision)

  190. Selkoe DJ (2008) Soluble oligomers of the amyloid beta-protein impair synaptic plasticity and behavior. Behav Brain Res 192:106–113

    PubMed  CAS  Google Scholar 

  191. Selkoe DJ (1994) Normal and abnormal biology of the beta-amyloid precursor protein. Annu Rev Neurosci 17:489–517

    PubMed  CAS  Google Scholar 

  192. Shankar GM, Li S, Mehta TH, Garcia-Munoz A, Shepardson NE, Smith I, Brett FM, Farrell MA, Rowan MJ, Lemere CA, Regan CM, Walsh DM, Sabatini BL, Selkoe DJ (2008) Amyloid-beta protein dimers isolated directly from Alzheimer’s brains impair synaptic plasticity and memory. Nat Med 14:837–842

    PubMed  CAS  Google Scholar 

  193. Shigematsu K, McGeer PL, McGeer EG (1992) Localization of amyloid precursor protein in selective postsynaptic densities of rat cortical neurons. Brain Res 592:353–357

    PubMed  CAS  Google Scholar 

  194. Shimohama S, Fujimoto S, Sumida Y, Akagawa K, Shirao T, Matsuoka Y, Taniguchi T (1998) Differential expression of rat brain synaptic proteins in development and aging. Biochem Biophys Res Commun 251(1):394–398

    PubMed  CAS  Google Scholar 

  195. Shimohama S, Kamiya S, Taniguchi T, Akagawa K, Kimura J (1997) Differential involvement of synaptic vesicle and presynaptic plasma membrane proteins in Alzheimer’s disease. Biochem Biophys Res Commun 236(2):239–242

    PubMed  CAS  Google Scholar 

  196. Simpson IA, Chundu KR, Davies-Hill T, Honer WG, Davies P (1994) Decreased concentrations of GLUT1 and GLUT3 glucose transporters in the brains of patients with Alzheimer’s disease. Ann Neurol 35(5):546–551

    PubMed  CAS  Google Scholar 

  197. Slunt HH, Thinakaran G, Von Koch C, Lo AC, Tanzi RE, Sisodia SS (1994) Expression of a ubiquitous, cross-reactive homologue of the mouse beta-amyloid precursor protein (APP). J Biol Chem 269:2637–2644

    PubMed  CAS  Google Scholar 

  198. Smith-Swintosky VL, Pettigrew LC, Craddock SD, Culwell AR, Rydel RE, Mattson MP (1994) Secreted forms of beta-amyloid precursor protein protect against ischemic brain injury. J Neurochem 63:781–784

    Article  PubMed  CAS  Google Scholar 

  199. Sorg C, Riedl V, Mühlau M, Calhoun VD, Eichele T, Läer L, Drzezga A, Förstl H, Kurz A, Zimmer C, Wohlschläger AM (2007) Selective changes of resting-state networks in individuals at risk for Alzheimer’s disease. Proc Natl Acad Sci USA 104:18760–18765

    PubMed  CAS  Google Scholar 

  200. Sperling R (2007) Functional MRI studies of associative encoding in normal aging, mild cognitive impairment, and Alzheimer’s disease. Ann N Y Acad Sci 1097:146–155

    PubMed  Google Scholar 

  201. Stieler JT, Boerema AS, Bullmann T, Kohl F, Strijkstra AM, Barnes BM, Arendt T (2008) Activity-state profile of tau kinases in hibernating animals. In: Lovegrove BG, McKechnie AE (eds) Hypometabolism in animals: hibernation, torpor and cryobiology. University of KwaZulu-Nata, Pietermaritzburg, pp 133–142

    Google Scholar 

  202. Stieler JT, Bullmann T, Kohl F, Barnes BM, Arendt T (2009) PHF-like tau phosphorylation in mammalian hibernation is not associated with p25-formation. J Neural Transm 116(3):345–350

    PubMed  CAS  Google Scholar 

  203. Strijkstra AM, Hut RA, de Wilde MC, Stieler J, Van der Zee EA (2003) Hippocampal synaptophysin immunoreactivity is reduced during natural hypothermia in ground squirrels. Neurosci Lett 344:29–32

    PubMed  CAS  Google Scholar 

  204. Supekar K, Menon V, Rubin D, Musen M, Greicius MD (2008) Network analysis of intrinsic functional brain connectivity in Alzheimer’s disease. PLoS Comput Biol 4(6):e1000100

    PubMed  Google Scholar 

  205. Svennerholm L, Gottfries CG (1994) Membrane lipids, selectively diminished in Alzheimer brains, suggest synapse loss as a primary event in early-onset form (type I) and demyelination in late-onset form (type II). J Neurochem 62:1039–1047

    Article  PubMed  CAS  Google Scholar 

  206. Sze CI, Bi H, Kleinschmidt-DeMasters BK, Filley CM, Martin LJ (2000) Selective regional loss of exocytotic presynaptic vesicle proteins in Alzheimer’s disease brains. J Neurol Sci 175(2):81–90

    PubMed  CAS  Google Scholar 

  207. Sze CI, Troncoso JC, Kawas C, Mouton P, Price DL, Martin LJ (1997) Loss of the presynaptic vesicle protein synaptophysin in hippocampus correlates with cognitive decline in Alzheimer disease. J Neuropathol Exp Neurol 56(8):933–944

    PubMed  CAS  Google Scholar 

  208. Takahashi RH, Capetillo-Zarate E, Lin MT, Milner TA, Gouras GK (2008) Co-occurrence of Alzheimer’s disease beta-amyloid and tau pathologies at synapses. Neurobiol Aging 2008 Sep 2. [Epub ahead of print]

  209. Tanzi RE, Gusella JF, Watkins PC, Bruns GA, St George-Hyslop P, Van Keuren ML, Patterson D, Pagan S, Kurnit DM, Neve RL (1987) Amyloid beta protein gene: cDNA, mRNA distribution, and genetic linkage near the Alzheimer locus. Science 235:880–884

    PubMed  CAS  Google Scholar 

  210. Tanzi E (1893) I fatti e le induzioni nell’odierna istologia del sistema nervoso. Rivista Sperimentale di Frenetria e Medicina Legale della Alienzioni mentali 19:419–472

    Google Scholar 

  211. 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(4):572–580

    PubMed  CAS  Google Scholar 

  212. Terry RD (1996) The pathogenesis of Alzheimer disease: an alternative to the amyloid hypothesis. J Neuropathol Exp Neurol 55(10):1023–1025

    PubMed  CAS  Google Scholar 

  213. Thornton E, Vink R, Blumbergs PC, Van Den Heuvel C (2006) Soluble amyloid precursor protein alpha reduces neuronal injury and improves functional outcome following diffuse traumatic brain injury in rats. Brain Res 1094:38–46

    PubMed  CAS  Google Scholar 

  214. Torroja L, Packard M, Gorczyca M, White K, Budnik V (1999) The Drosophila beta-amyloid precursor protein homolog promotes synapse differentiation at the neuromuscular junction. J Neurosci 19:7793–7803

    PubMed  CAS  Google Scholar 

  215. van Gehuchten A (1900) Anatomie du systéme nerveux de l’homme. 3rd edn. Louvain

  216. Villa A, Latasa MJ, Pascual A (2001) Nerve growth factor modulates the expression and secretion of beta-amyloid precursor protein through different mechanisms in PC12 cells. J Neurochem 77:1077–1084

    PubMed  CAS  Google Scholar 

  217. Vincent I, Rosado M, Davies P (1996) Mitotic mechanisms in Alzheimer’s disease? J Cell Biol 132:413–425

    PubMed  CAS  Google Scholar 

  218. von der Ohe CG, Garner CC, Darian-Smith C, Heller HC (2007) Synaptic protein dynamics in hibernation. J Neurosci 27:84–92

    Google Scholar 

  219. von Koch CS, Zheng H, Chen H, Trumbauer M, Thinakaran G, van der Ploeg LH, Price DL, Sisodia SS (1997) Generation of APLP2 KO mice and early postnatal lethality in APLP2/APP double KO mice. Neurobiol Aging 18:661–669

    Google Scholar 

  220. von Kölliker (1895) Kritik der Hypothesen von Rabl-Rückhard und Duval über amoeboide Bewegungen der Neurodendren. Sitzungsberichte der physik.-med. Gesellschaft: 38-42

  221. Wakabayashi K, Honer WG, Masliah E (1994) Synapse alterations in the hippocampal-entorhinal formation in Alzheimer’s disease with and without Lewy body disease. Brain Res 667(1):24–32

    PubMed  CAS  Google Scholar 

  222. Walsh DM, Klyubin I, Fadeeva JV, Cullen WK, Anwyl R, Wolfe MS, Rowan MJ, Selkoe DJ (2002) Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature 416:535–539

    PubMed  CAS  Google Scholar 

  223. Walsh DM, Selkoe DJ (2004) Deciphering the molecular basis of memory failure in Alzheimer’s disease. Neuron 44:181–193

    PubMed  CAS  Google Scholar 

  224. Wang L, Zang Y, He Y, Liang M, Zhang X, Tian L, Wu T, Jiang T, Li K (2006) Changes in hippocampal connectivity in the early stages of Alzheimer’s disease: evidence from resting state fMRI. Neuroimage 31:496–504

    PubMed  Google Scholar 

  225. Wang P, Yang G, Mosier DR, Chang P, Zaidi T, Gong YD, Zhao NM, Dominguez B, Lee KF, Gan WB, Zheng H (2005) Defective neuromuscular synapses in mice lacking amyloid precursor protein (APP) and APP-like protein 2. J Neurosci 25:1219–1225

    PubMed  CAS  Google Scholar 

  226. Wasco W, Bupp K, Magendantz M, Gusella JF, Tanzi RE, Solomon F (1992) Identification of a mouse brain cDNA that encodes a protein related to the Alzheimer disease-associated amyloid beta protein precursor. PNAS 89:10758–10762

    PubMed  CAS  Google Scholar 

  227. Wasco W, Gurubhagavatula S, Paradis MD, Romano DM, Sisodia SS, Hyman BT, Neve RL, Tanzi RE (1993) Isolation and characterization of APLP2 encoding a homologue of the Alzheimer’s associated amyloid beta protein precursor. Nat Genet 5:95–100

    PubMed  CAS  Google Scholar 

  228. Weiler R, Lassmann H, Fischer P, Jellinger K, Winkler H (1990) A high ratio of chromogranin A to synaptin/synaptophysin is a common feature of brains in Alzheimer and Pick disease. FEBS Lett 263:337–339

    PubMed  CAS  Google Scholar 

  229. Yamazaki T, Selkoe DJ, Koo EH (1995) Trafficking of cell surface beta-amyloid precursor protein: retrograde and transcytotic transport in cultured neurons. J Cell Biol 129:431–442

    PubMed  CAS  Google Scholar 

  230. Yang G, Gong YD, Gong K, Jiang WL, Kwon E, Wang P, Zheng H, Zhang XF, Gan WB, Zhao NM (2005) Reduced synaptic vesicle density and active zone size in mice lacking amyloid precursor protein (APP) and APP-like protein 2. Neurosci Lett 384:66–71

    PubMed  CAS  Google Scholar 

  231. Yankner BA, Duffy LK, Kirschner DA (1990) Neurotrophic and neurotoxic effects of amyloid beta protein: reversal by tachykinin neuropeptides. Science 250:279–282

    PubMed  CAS  Google Scholar 

  232. Yao PJ, Morsch R, Callahan LM, Coleman PD (1999) Changes in synaptic expression of clathrin assembly protein AP180 in Alzheimer’s disease analysed by immunohistochemistry. Neuroscience 94:389–394

    PubMed  CAS  Google Scholar 

  233. Yao PJ, Zhu M, Pyun EI, Brooks AI, Therianos S, Meyers VE, Coleman PD (2003) Defects in expression of genes related to synaptic vesicle trafficking in frontal cortex of Alzheimer’s disease. Neurobiol Dis 12(2):97–109

    PubMed  CAS  Google Scholar 

  234. Zampieri N, Xu CF, Neubert TA, Chao MV (2005) Cleavage of p75 neurotrophin receptor by alpha-secretase and gamma-secretase requires specific receptor domains. J Biol Chem 280:14563–14571

    PubMed  CAS  Google Scholar 

  235. Zhan SS, Beyreuther K, Schmitt HP (1993) Quantitative assessment of the synaptophysin immuno-reactivity of the cortical neuropil in various neurodegenerative disorders with dementia. Dementia 4:66–74

    PubMed  CAS  Google Scholar 

  236. Zhan SS, Beyreuther K, Schmitt HP (1994) Synaptophysin immunoreactivity of the cortical neuropil in vascular dementia of Binswanger type compared with the dementia of Alzheimer type and nondemented controls. Dementia 5:79–87

    PubMed  CAS  Google Scholar 

  237. Zheng H, Jiang M, Trumbauer ME, Sirinathsinghji DJ, Hopkins R, Smith DW, Heavens RP, Dawson GR, Boyce S, Conner MW, Stevens KA, Slunt HH, Sisoda SS, Chen HY, Van der Ploeg LH (1995) Beta-amyloid precursor protein-deficient mice show reactive gliosis and decreased locomotor activity. Cell 81:525–531

    PubMed  CAS  Google Scholar 

  238. Zubenko GS, Kopp U, Seto T, Firestone LL (1999) Platelet membrane fluidity individuals at risk for Alzheimer’s disease: a comparison of results from fluorescence spectroscopy and electron spin resonance spectroscopy. Psychopharmacology (Berl.) 145:175–180

    CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Paul Flechsig Institute of Brain Research, University of Leipzig, Jahnallee 59, 04109, Leipzig, Germany

    Thomas Arendt

Authors
  1. Thomas Arendt
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Thomas Arendt.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Arendt, T. Synaptic degeneration in Alzheimer’s disease. Acta Neuropathol 118, 167–179 (2009). https://doi.org/10.1007/s00401-009-0536-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00401-009-0536-x

Keywords

Search

Navigation