Skip to main content

Advertisement

Log in

Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease

Acta Neuropathologica Aims and scope Submit manuscript

Abstract

The aberrant accumulation of aggregated β-amyloid peptides (Aβ) as plaques is a hallmark of Alzheimer’s disease (AD) neuropathology and reduction of Aβ has become a leading direction of emerging experimental therapies for the disease. The mechanism(s) whereby Aβ is involved in the pathophysiology of the disease remain(s) poorly understood. Initially fibrils, and subsequently oligomers of extracellular Aβ have been viewed as the most important pathogenic form of Aβ in AD. More recently, the intraneuronal accumulation of Aβ has been described in the brain, although technical considerations and its relevance in AD have made this a controversial topic. Here, we review the emerging evidence linking intraneuronal Aβ accumulation to the development of synaptic pathology and plaques in AD, and discuss the implications of intraneuronal β-amyloid for AD pathology, biology, diagnosis and therapy.

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

Access this article

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

Similar content being viewed by others

References

  1. Alafuzoff I, Pikkarainen M, Arzberger T et al (2008) Inter-laboratory comparison of neuropathological assessments of beta-amyloid protein: a study of the BrainNet Europe consortium. Acta Neuropathol 115:533–546

    CAS  PubMed  Google Scholar 

  2. Almeida CG, Takahashi RH, Gouras GK (2006) Beta-amyloid accumulation impairs multivesicular body sorting by inhibiting the ubiquitin-proteasome system. J Neurosci 26:4277–4288

    CAS  PubMed  Google Scholar 

  3. Almeida CG, Tampellini D, Takahashi RH et al (2005) Beta-amyloid accumulation in APP mutant neurons reduces PSD-95 and GluR1 in synapses. Neurobiol Dis 20:187–198

    CAS  PubMed  Google Scholar 

  4. Allsop D, Haga S, Bruton C, Ishii T, Roberts GW (1990) Neurofibrillary tangles in some cases of dementia pugilistica share antigens with amyloid beta-protein of Alzheimer’s disease. Am J Pathol 136:255–260

    CAS  PubMed  Google Scholar 

  5. Aoki M, Volkmann I, Tjernberg LO, Winblad B, Bogdanovic N (2008) Amyloid beta-peptide levels in laser capture microdissected cornu ammonis 1 pyramidal neurons of Alzheimer’s brain. Neuroreport 19:1085–1089

    CAS  PubMed  Google Scholar 

  6. Arendt T (2009) Synaptic degeneration in Alzheimer’s disease. Acta Neuropathol 118:167–179

    PubMed  Google Scholar 

  7. Bancher C, Grundke-Iqbal I, Iqbal K, Kim KS, Wisniewski HM (1989) Immunoreactivity of neuronal lipofuscin with monoclonal antibodies to the amyloid beta-protein. Neurobiol Aging 10:125–132

    CAS  PubMed  Google Scholar 

  8. Bard F, Cannon C, Barbour R et al (2000) Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nat Med 6:916–919

    CAS  PubMed  Google Scholar 

  9. Bayer A, Wirths O (2010) Intracellular accumulation of amyloid-beta—a predictor for synaptic dysfunction and neuron loss in Alzheimer’s disease. Front Ag Neurosci 2:8. doi:103389/fnagi201000008

    Google Scholar 

  10. Bence NF, Sampat RM, Kopito RR (2001) Impairment of the ubiquitin-proteasome system by protein aggregation. Science 292:1552–1555

    CAS  PubMed  Google Scholar 

  11. Bertram L, Tanzi RE (2008) Thirty years of Alzheimer’s disease genetics: the implications of systematic meta-analyses. Nat Rev Neurosci 9:768–778

    CAS  PubMed  Google Scholar 

  12. Billings LM, Oddo S, Green KN, McGaugh JL, LaFerla FM (2005) Intraneuronal Abeta causes the onset of early Alzheimer’s disease-related cognitive deficits in transgenic mice. Neuron 45:675–688

    CAS  PubMed  Google Scholar 

  13. Bittner T, Fuhrmann M, Burgold S et al (2009) Gamma-secretase inhibition reduces spine density in vivo via an amyloid precursor protein-dependent pathway. J Neurosci 29:10405–10409

    CAS  PubMed  Google Scholar 

  14. Blanchard V, Moussaoui S, Czech C et al (2003) Time sequence of maturation of dystrophic neurites associated with Abeta deposits in APP/PS1 transgenic mice. Exp Neurol 184:247–263

    CAS  PubMed  Google Scholar 

  15. Blennow K, Hampel H, Weiner M, Zetterberg H (2010) Cerebrospinal fluid and plasma biomarkers in Alzheimer disease. Nat Rev Neurol 6:131–144

    CAS  PubMed  Google Scholar 

  16. Brody DL, Magnoni S, Schwetye KE et al (2008) Amyloid-beta dynamics correlate with neurological status in the injured human brain. Science 321:1221–1224

    CAS  PubMed  Google Scholar 

  17. Bu G (2009) Apolipoprotein E and its receptors in Alzheimer’s disease: pathways, pathogenesis and therapy. Nat Rev Neurosci 10:333–344

    CAS  PubMed  Google Scholar 

  18. Buckner RL, Snyder AZ, Shannon BJ et al (2005) Molecular, structural, and functional characterization of Alzheimer’s disease: evidence for a relationship between default activity, amyloid, and memory. J Neurosci 25:7709–7717

    CAS  PubMed  Google Scholar 

  19. Busciglio J, Pelsman A, Wong C et al (2002) Altered metabolism of the amyloid beta precursor protein is associated with mitochondrial dysfunction in Down’s syndrome. Neuron 33:677–688

    CAS  PubMed  Google Scholar 

  20. Caccamo A, Oddo S, Sugarman MC, Akbari Y, LaFerla FM (2005) Age- and region-dependent alterations in Abeta-degrading enzymes: implications for Abeta-induced disorders. Neurobiol Aging 26:645–654

    CAS  PubMed  Google Scholar 

  21. Cai H, Wang Y, McCarthy D et al (2001) BACE1 is the major beta-secretase for generation of Abeta peptides by neurons. Nat Neurosci 4:233–234

    CAS  PubMed  Google Scholar 

  22. Capetillo-Zarate E, Staufenbiel M, Abramowski D et al (2006) Selective vulnerability of different types of commissural neurons for amyloid {beta}-protein-induced neurodegeneration in APP23 mice correlates with dendritic tree morphology. Brain 129:2992–3005

    PubMed  Google Scholar 

  23. Casas C, Sergeant N, Itier JM et al (2004) Massive CA1/2 neuronal loss with intraneuronal and N-terminal truncated Abeta42 accumulation in a novel Alzheimer transgenic model. Am J Pathol 165:1289–1300

    CAS  PubMed  Google Scholar 

  24. Cataldo AM, Petanceska S, Terio NB et al (2004) Abeta localization in abnormal endosomes: association with earliest Abeta elevations in AD and Down syndrome. Neurobiol Aging 25:1263–1272

    CAS  PubMed  Google Scholar 

  25. Cirrito JR, Kang JE, Lee J et al (2008) Endocytosis is required for synaptic activity-dependent release of amyloid-beta in vivo. Neuron 58:42–51

    CAS  PubMed  Google Scholar 

  26. Cirrito JR, Yamada KA, Finn MB et al (2005) Synaptic activity regulates interstitial fluid amyloid-beta levels in vivo. Neuron 48:913–922

    CAS  PubMed  Google Scholar 

  27. Clinton J, Ambler MW, Roberts GW (1991) Post-traumatic Alzheimer’s disease: preponderance of a single plaque type. Neuropathol Appl Neurobiol 17:69–74

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  29. Cooney JR, Hurlburt JL, Selig DK, Harris KM, Fiala JC (2002) Endosomal compartments serve multiple hippocampal dendritic spines from a widespread rather than a local store of recycling membrane. J Neurosci 22:2215–2224

    CAS  PubMed  Google Scholar 

  30. Corder EH, Saunders AM, Strittmatter WJ et al (1993) Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 261:921–923

    CAS  PubMed  Google Scholar 

  31. Corsellis JA, Bruton CJ, Freeman-Browne D (1973) The aftermath of boxing. Psychol Med 3:270–303

    CAS  PubMed  Google Scholar 

  32. Chapman PF, White GL, Jones MW et al (1999) Impaired synaptic plasticity and learning in aged amyloid precursor protein transgenic mice. Nat Neurosci 2:271–276

    CAS  PubMed  Google Scholar 

  33. Chen X, Yan SD (2006) Mitochondrial Abeta: a potential cause of metabolic dysfunction in Alzheimer’s disease. IUBMB Life 58:686–694

    CAS  PubMed  Google Scholar 

  34. Christensen DZ, Bayer TA, Wirths O (2009) Formic acid is essential for immunohistochemical detection of aggregated intraneuronal Abeta peptides in mouse models of Alzheimer’s disease. Brain Res 1301:116–125

    CAS  PubMed  Google Scholar 

  35. Christensen DZ, Kraus SL, Flohr A, Cotel MC, Wirths O, Bayer TA (2008) Transient intraneuronal A beta rather than extracellular plaque pathology correlates with neuron loss in the frontal cortex of APP/PS1KI mice. Acta Neuropathol 116:647–655

    CAS  PubMed  Google Scholar 

  36. Chui DH, Tanahashi H, Ozawa K et al (1999) Transgenic mice with Alzheimer presenilin 1 mutations show accelerated neurodegeneration without amyloid plaque formation. Nat Med 5:560–564

    CAS  PubMed  Google Scholar 

  37. D’Andrea M, Nagele R (2010) Morphologically distinct types of amyloid plaques point the way to a better understanding of Alzheimer’s disease pathogenesis. Biotech Histochem. doi:103109/10520290903389445

  38. D’Andrea MR, Nagele RG, Wang HY, Peterson PA, Lee DH (2001) Evidence that neurones accumulating amyloid can undergo lysis to form amyloid plaques in Alzheimer’s disease. Histopathology 38:120–134

    PubMed  Google Scholar 

  39. D’Andrea MR, Reiser PA, Polkovitch DA et al (2003) The use of formic acid to embellish amyloid plaque detection in Alzheimer’s disease tissues misguides key observations. Neurosci Lett 342:114–118

    PubMed  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

    CAS  PubMed  Google Scholar 

  41. De Strooper B, Vassar R, Golde T (2010) The secretases: enzymes with therapeutic potential in Alzheimer disease. Nat Rev Neurol 6:99–107

    PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  43. Deshpande A, Kawai H, Metherate R, Glabe CG, Busciglio J (2009) A role for synaptic zinc in activity-dependent Abeta oligomer formation and accumulation at excitatory synapses. J Neurosci 29:4004–4015

    CAS  PubMed  Google Scholar 

  44. Duyckaerts C, Delatour B, Potier MC (2009) Classification and basic pathology of Alzheimer disease. Acta Neuropathol 118:5–36

    CAS  PubMed  Google Scholar 

  45. Echeverria V, Cuello AC (2002) Intracellular A-beta amyloid, a sign for worse things to come? Mol Neurobiol 26:299–316

    CAS  PubMed  Google Scholar 

  46. Ehlers MD (2003) Activity level controls postsynaptic composition and signaling via the ubiquitin-proteasome system. Nat Neurosci 6:231–242

    CAS  PubMed  Google Scholar 

  47. Espana J, Gimenez-Llort L, Valero J et al (2010) Intraneuronal beta-amyloid accumulation in the amygdala enhances fear and anxiety in Alzheimer’s disease transgenic mice. Biol Psychiatry 67:513–521

    CAS  PubMed  Google Scholar 

  48. Fagan AM, Head D, Shah AR et al (2009) Decreased cerebrospinal fluid Abeta(42) correlates with brain atrophy in cognitively normal elderly. Ann Neurol 65:176–183

    CAS  PubMed  Google Scholar 

  49. Friedrich RP, Tepper K, Ronicke R et al (2010) Mechanism of amyloid plaque formation suggests an intracellular basis of A{beta} pathogenicity. Proc Natl Acad Sci USA 107:1942–1947

    CAS  PubMed  Google Scholar 

  50. Fukami S, Watanabe K, Iwata N et al (2002) Abeta-degrading endopeptidase, neprilysin, in mouse brain: synaptic and axonal localization inversely correlating with Abeta pathology. Neurosci Res 43:39–56

    CAS  PubMed  Google Scholar 

  51. Glabe C (2001) Intracellular mechanisms of amyloid accumulation and pathogenesis in Alzheimer’s disease. J Mol Neurosci 17:137–145

    CAS  PubMed  Google Scholar 

  52. Goate AM, Haynes AR, Owen MJ et al (1989) Predisposing locus for Alzheimer’s disease on chromosome 21. Lancet 1:352–355

    CAS  PubMed  Google Scholar 

  53. Golde TE, Das P, Levites Y (2009) Quantitative and mechanistic studies of Abeta immunotherapy. CNS Neurol Disord Drug Targets 8:31–49

    CAS  PubMed  Google Scholar 

  54. Goldsbury C, Mocanu MM, Thies E et al (2006) Inhibition of APP trafficking by tau protein does not increase the generation of amyloid-beta peptides. Traffic 7:873–888

    CAS  PubMed  Google Scholar 

  55. Gortz N, Lewejohann L, Tomm M et al (2008) Effects of environmental enrichment on exploration, anxiety, and memory in female TgCRND8 Alzheimer mice. Behav Brain Res 191:43–48

    PubMed  Google Scholar 

  56. Gotz J, Chen F, van Dorpe J, Nitsch RM (2001) Formation of neurofibrillary tangles in P301l tau transgenic mice induced by Abeta 42 fibrils. Science 293:1491–1495

    CAS  PubMed  Google Scholar 

  57. Gouras GK, Takahashi RH (2005) Immunohistocytochemical analysis of amyloid precursor protein and its derivates. In: Xia W, Xu H (eds) Amyloid precursor protein: a practical approach. CRC Press, Florida, pp 155–160

    Google Scholar 

  58. Gouras GK, Almeida CG, Takahashi RH (2005) Intraneuronal Abeta accumulation and origin of plaques in Alzheimer’s disease. Neurobiol Aging 26:1235–1244

    CAS  PubMed  Google Scholar 

  59. Gouras GK, Xu H, Jovanovic JN et al (1998) Generation and regulation of beta-amyloid peptide variants by neurons. J Neurochem 71:1920–1925

    Article  CAS  PubMed  Google Scholar 

  60. Gouras GK, Tsai J, Naslund J et al (2000) Intraneuronal Abeta42 accumulation in human brain. Am J Pathol 156:15–20

    CAS  PubMed  Google Scholar 

  61. Grinberg LT, Thal DR (2010) Vascular pathology in the aged human brain. Acta Neuropathol 119:277–290

    PubMed  Google Scholar 

  62. Grundke-Iqbal I, Iqbal K, George L, Tung YC, Kim KS, Wisniewski HM (1989) Amyloid protein and neurofibrillary tangles coexist in the same neuron in Alzheimer disease. Proc Natl Acad Sci USA 86:2853–2857

    CAS  PubMed  Google Scholar 

  63. Gylys KH, Fein JA, Yang F, Wiley DJ, Miller CA, Cole GM (2004) Synaptic changes in Alzheimer’s disease: increased amyloid-beta and gliosis in surviving terminals is accompanied by decreased PSD-95 fluorescence. Am J Pathol 165:1809–1817

    CAS  PubMed  Google Scholar 

  64. Gyure KA, Durham R, Stewart WF, Smialek JE, Troncoso JC (2001) Intraneuronal abeta-amyloid precedes development of amyloid plaques in Down syndrome. Arch Pathol Lab Med 125:489–492

    CAS  PubMed  Google Scholar 

  65. 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

    CAS  PubMed  Google Scholar 

  66. Hampel H, Teipel SJ, Fuchsberger T et al (2004) Value of CSF beta-amyloid1–42 and tau as predictors of Alzheimer’s disease in patients with mild cognitive impairment. Mol Psychiatry 9:705–710

    CAS  PubMed  Google Scholar 

  67. Hansson Petersen CA, Alikhani N, Behbahani H et al (2008) The amyloid beta-peptide is imported into mitochondria via the TOM import machinery and localized to mitochondrial cristae. Proc Natl Acad Sci USA 105:13145–13150

    CAS  PubMed  Google Scholar 

  68. Harigaya Y, Saido TC, Eckman CB, Prada CM, Shoji M, Younkin SG (2000) Amyloid beta protein starting pyroglutamate at position 3 is a major component of the amyloid deposits in the Alzheimer’s disease brain. Biochem Biophys Res Commun 276:422–427

    CAS  PubMed  Google Scholar 

  69. Hartmann T (1999) Intracellular biology of Alzheimer’s disease amyloid beta peptide. Eur Arch Psychiatry Clin Neurosci 249:291–298

    CAS  PubMed  Google Scholar 

  70. Hashimoto M, Bogdanovic N, Volkmann I, Aoki M, Winblad B, Tjernberg LO (2010) Analysis of microdissected human neurons by a sensitive ELISA reveals a correlation between elevated intracellular concentrations of Abeta42 and Alzheimer’s disease neuropathology. Acta Neuropathol. doi:101007/s00401-010-0661-6

  71. Hecimovic S, Wang J, Dolios G, Martinez M, Wang R, Goate AM (2004) Mutations in APP have independent effects on Abeta and CTFgamma generation. Neurobiol Dis 17:205–218

    CAS  PubMed  Google Scholar 

  72. Heneka MT, Ramanathan M, Jacobs AH et al (2006) Locus ceruleus degeneration promotes Alzheimer pathogenesis in amyloid precursor protein 23 transgenic mice. J Neurosci 26:1343–1354

    CAS  PubMed  Google Scholar 

  73. Herzig MC, Winkler DT, Burgermeister P et al (2004) Abeta is targeted to the vasculature in a mouse model of hereditary cerebral hemorrhage with amyloidosis. Nat Neurosci 7:954–960

    CAS  PubMed  Google Scholar 

  74. Holcomb L, Gordon MN, McGowan E et al (1998) Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenes. Nat Med 4:97–100

    CAS  PubMed  Google Scholar 

  75. Holmes C, Boche D, Wilkinson D et al (2008) Long-term effects of Abeta42 immunisation in Alzheimer’s disease: follow-up of a randomised, placebo-controlled phase I trial. Lancet 372:216–223

    CAS  PubMed  Google Scholar 

  76. Horikoshi Y, Sakaguchi G, Becker AG et al (2004) Development of Abeta terminal end-specific antibodies and sensitive ELISA for Abeta variant. Biochem Biophys Res Commun 319:733–737

    CAS  PubMed  Google Scholar 

  77. Hsia AY, Masliah E, McConlogue L et al (1999) Plaque-independent disruption of neural circuits in Alzheimer’s disease mouse models. Proc Natl Acad Sci USA 96:3228–3233

    CAS  PubMed  Google Scholar 

  78. Hsiao K, Chapman P, Nilsen S et al (1996) Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice. Science 274:99–102

    CAS  PubMed  Google Scholar 

  79. Hsieh H, Boehm J, Sato C et al (2006) AMPAR removal underlies Abeta-induced synaptic depression and dendritic spine loss. Neuron 52:831–843

    CAS  PubMed  Google Scholar 

  80. Hyman BT, Van Hoesen GW, Beyreuther K, Masters CL (1989) A4 amyloid protein immunoreactivity is present in Alzheimer’s disease neurofibrillary tangles. Neurosci Lett 101:352–355

    CAS  PubMed  Google Scholar 

  81. Iwata N, Tsubuki S, Takaki Y et al (2000) Identification of the major Abeta1-42-degrading catabolic pathway in brain parenchyma: suppression leads to biochemical and pathological deposition. Nat Med 6:143–150

    CAS  PubMed  Google Scholar 

  82. Iwatsubo T, Odaka A, Suzuki N, Mizusawa H, Nukina N, Ihara Y (1994) Visualization of A beta 42(43) and A beta 40 in senile plaques with end-specific A beta monoclonals: evidence that an initially deposited species is A beta 42(43). Neuron 13:45–53

    CAS  PubMed  Google Scholar 

  83. Jack CR Jr, Knopman DS, Jagust WJ et al (2010) Hypothetical model of dynamic biomarkers of the Alzheimer’s pathological cascade. Lancet Neurol 9:119–128

    CAS  PubMed  Google Scholar 

  84. Jin LW, Shie FS, Maezawa I, Vincent I, Bird T (2004) Intracellular accumulation of amyloidogenic fragments of amyloid-beta precursor protein in neurons with Niemann-Pick type C defects is associated with endosomal abnormalities. Am J Pathol 164:975–985

    CAS  PubMed  Google Scholar 

  85. Kamenetz F, Tomita T, Hsieh H et al (2003) APP processing and synaptic function. Neuron 37:925–937

    CAS  PubMed  Google Scholar 

  86. Kawarabayashi T, Younkin LH, Saido TC, Shoji M, Ashe KH, Younkin SG (2001) Age-dependent changes in brain, CSF, and plasma amyloid (beta) protein in the Tg2576 transgenic mouse model of Alzheimer’s disease. J Neurosci 21:372–381

    CAS  PubMed  Google Scholar 

  87. Kayed R, Head E, Sarsoza F et al (2007) Fibril specific, conformation dependent antibodies recognize a generic epitope common to amyloid fibrils and fibrillar oligomers that is absent in prefibrillar oligomers. Mol Neurodegener 2:18

    PubMed  Google Scholar 

  88. Kim J, Basak JM, Holtzman DM (2009) The role of apolipoprotein E in Alzheimer’s disease. Neuron 63:287–303

    CAS  PubMed  Google Scholar 

  89. Knobloch M, Konietzko U, Krebs DC, Nitsch RM (2007) Intracellular Abeta and cognitive deficits precede beta-amyloid deposition in transgenic arcAbeta mice. Neurobiol Aging 28:1297–1306

    CAS  PubMed  Google Scholar 

  90. Kumar-Singh S, De Jonghe C, Cruts M et al (2000) Nonfibrillar diffuse amyloid deposition due to a gamma(42)-secretase site mutation points to an essential role for N-truncated A beta(42) in Alzheimer’s disease. Hum Mol Genet 9:2589–2598

    CAS  PubMed  Google Scholar 

  91. Lacor PN, Buniel MC, Chang L et al (2004) Synaptic targeting by Alzheimer’s-related amyloid beta oligomers. J Neurosci 24:10191–10200

    CAS  PubMed  Google Scholar 

  92. LaFerla FM, Green KN, Oddo S (2007) Intracellular amyloid-beta in Alzheimer’s disease. Nat Rev Neurosci 8:499–509

    CAS  PubMed  Google Scholar 

  93. LaFerla FM, Tinkle BT, Bieberich CJ, Haudenschild CC, Jay G (1995) The Alzheimer’s A beta peptide induces neurodegeneration and apoptotic cell death in transgenic mice. Nat Genet 9:21–30

    CAS  PubMed  Google Scholar 

  94. Lah JJ, Heilman CJ, Nash NR et al (1997) Light and electron microscopic localization of presenilin-1 in primate brain. J Neurosci 17:1971–1980

    CAS  PubMed  Google Scholar 

  95. Langui D, Girardot N, El Hachimi KH et al (2004) Subcellular topography of neuronal Abeta peptide in APPxPS1 transgenic mice. Am J Pathol 165:1465–1477

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  97. Lazarov O, Robinson J, Tang YP et al (2005) Environmental enrichment reduces Abeta levels and amyloid deposition in transgenic mice. Cell 120:701–713

    CAS  PubMed  Google Scholar 

  98. Lemere CA, Blusztajn JK, Yamaguchi H, Wisniewski T, Saido TC, Selkoe DJ (1996) Sequence of deposition of heterogeneous amyloid beta-peptides and APO E in Down syndrome: implications for initial events in amyloid plaque formation. Neurobiol Dis 3:16–32

    CAS  PubMed  Google Scholar 

  99. Leon WC, Canneva F, Partridge V et al (2010) A novel transgenic rat model with a full Alzheimer’s-like amyloid pathology displays pre-plaque intracellular amyloid-beta-associated cognitive impairment. J Alzheimers Dis. doi:103233/JAD-2010-1349

  100. Lesne S, Koh MT, Kotilinek L et al (2006) A specific amyloid-beta protein assembly in the brain impairs memory. Nature 440:352–357

    CAS  PubMed  Google Scholar 

  101. Lewis J, Dickson DW, Lin WL et al (2001) Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP. Science 293:1487–1491

    CAS  PubMed  Google Scholar 

  102. Li F, Calingasan NY, Yu F et al (2004) Increased plaque burden in brains of APP mutant MnSOD heterozygous knockout mice. J Neurochem 89:1308–1312

    CAS  PubMed  Google Scholar 

  103. Lin MT, Beal MF (2006) Alzheimer’s APP mangles mitochondria. Nat Med 12:1241–1243

    CAS  PubMed  Google Scholar 

  104. Lin MT, Beal MF (2006) Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443:787–795

    CAS  PubMed  Google Scholar 

  105. Longva KE, Blystad FD, Stang E, Larsen AM, Johannessen LE, Madshus IH (2002) Ubiquitination and proteasomal activity is required for transport of the EGF receptor to inner membranes of multivesicular bodies. J Cell Biol 156:843–854

    CAS  PubMed  Google Scholar 

  106. Lord A, Kalimo H, Eckman C, Zhang XQ, Lannfelt L, Nilsson LN (2006) The Arctic Alzheimer mutation facilitates early intraneuronal Abeta aggregation and senile plaque formation in transgenic mice. Neurobiol Aging 27:67–77

    CAS  PubMed  Google Scholar 

  107. Lorenzo A, Yuan M, Zhang Z et al (2000) Amyloid beta interacts with the amyloid precursor protein: a potential toxic mechanism in Alzheimer’s disease. Nat Neurosci 3:460–464

    CAS  PubMed  Google Scholar 

  108. Lue LF, Kuo YM, Roher AE et al (1999) Soluble amyloid beta peptide concentration as a predictor of synaptic change in Alzheimer’s disease. Am J Pathol 155:853–862

    CAS  PubMed  Google Scholar 

  109. Lustbader JW, Cirilli M, Lin C et al (2004) ABAD directly links Abeta to mitochondrial toxicity in Alzheimer’s disease. Science 304:448–452

    CAS  PubMed  Google Scholar 

  110. Mackenzie IR, Miller LA (1994) Senile plaques in temporal lobe epilepsy. Acta Neuropathol 87:504–510

    CAS  PubMed  Google Scholar 

  111. Mahley RW, Weisgraber KH, Huang Y (2009) Apolipoprotein E: structure determines function, from atherosclerosis to Alzheimer’s disease to AIDS. J Lipid Res 50(Suppl):S183–S188

    PubMed  Google Scholar 

  112. Masliah E, Crews L, Hansen L (2006) Synaptic remodeling during aging and in Alzheimer’s disease. J Alzheimers Dis 9:91–99

    CAS  PubMed  Google Scholar 

  113. 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 174:67–72

    CAS  PubMed  Google Scholar 

  114. Masliah E, Sisk A, Mallory M, Mucke L, Schenk D, Games D (1996) Comparison of neurodegenerative pathology in transgenic mice overexpressing V717F beta-amyloid precursor protein and Alzheimer’s disease. J Neurosci 16:5795–5811

    CAS  PubMed  Google Scholar 

  115. Masters CL, Multhaup G, Simms G, Pottgiesser J, Martins RN, Beyreuther K (1985) Neuronal origin of a cerebral amyloid: neurofibrillary tangles of Alzheimer’s disease contain the same protein as the amyloid of plaque cores and blood vessels. EMBO J 4:2757–2763

    CAS  PubMed  Google Scholar 

  116. Mayeux R, Ottman R, Tang MX et al (1993) Genetic susceptibility and head injury as risk factors for Alzheimer’s disease among community-dwelling elderly persons and their first-degree relatives. Ann Neurol 33:494–501

    CAS  PubMed  Google Scholar 

  117. McGowan E, Pickford F, Kim J et al (2005) Abeta42 is essential for parenchymal and vascular amyloid deposition in mice. Neuron 47:191–199

    CAS  PubMed  Google Scholar 

  118. McLean CA, Cherny RA, Fraser FW et al (1999) Soluble pool of Abeta amyloid as a determinant of severity of neurodegeneration in Alzheimer’s disease. Ann Neurol 46:860–866

    CAS  PubMed  Google Scholar 

  119. Mesulam MM (1999) Neuroplasticity failure in Alzheimer’s disease: bridging the gap between plaques and tangles. Neuron 24:521–529

    CAS  PubMed  Google Scholar 

  120. Meyer-Luehmann M, Spires-Jones TL, Prada C et al (2008) Rapid appearance and local toxicity of amyloid-beta plaques in a mouse model of Alzheimer’s disease. Nature 451:720–724

    CAS  PubMed  Google Scholar 

  121. Meyer-Luehmann M, Coomaraswamy J, Bolmont T et al (2006) Exogenous induction of cerebral beta-amyloidogenesis is governed by agent and host. Science 313:1781–1784

    CAS  PubMed  Google Scholar 

  122. Miller SL, Celone K, DePeau K et al (2008) Age-related memory impairment associated with loss of parietal deactivation but preserved hippocampal activation. Proc Natl Acad Sci USA 105:2181–2186

    CAS  PubMed  Google Scholar 

  123. Mochizuki A, Tamaoka A, Shimohata A, Komatsuzaki Y, Shoji S (2000) Abeta42-positive non-pyramidal neurons around amyloid plaques in Alzheimer’s disease. Lancet 355:42–43

    CAS  PubMed  Google Scholar 

  124. Moechars D, Dewachter I, Lorent K et al (1999) Early phenotypic changes in transgenic mice that overexpress different mutants of amyloid precursor protein in brain. J Biol Chem 274:6483–6492

    CAS  PubMed  Google Scholar 

  125. Moolman DL, Vitolo OV, Vonsattel JP, Shelanski ML (2004) Dendrite and dendritic spine alterations in Alzheimer models. J Neurocytol 33:377–387

    CAS  PubMed  Google Scholar 

  126. Mori C, Spooner ET, Wisniewsk KE et al (2002) Intraneuronal Abeta42 accumulation in Down syndrome brain. Amyloid 9:88–102

    CAS  PubMed  Google Scholar 

  127. Mortimer JA, French LR, Hutton JT, Schuman LM (1985) Head injury as a risk factor for Alzheimer’s disease. Neurology 35:264–267

    CAS  PubMed  Google Scholar 

  128. Mrak RE, Griffin WS (2001) Interleukin-1, neuroinflammation, and Alzheimer’s disease. Neurobiol Aging 22:903–908

    CAS  PubMed  Google Scholar 

  129. Muresan V, Varvel NH, Lamb BT, Muresan Z (2009) The cleavage products of amyloid-beta precursor protein are sorted to distinct carrier vesicles that are independently transported within neurites. J Neurosci 29:3565–3578

    CAS  PubMed  Google Scholar 

  130. Naslund J, Haroutunian V, Mohs R et al (2000) Correlation between elevated levels of amyloid beta-peptide in the brain and cognitive decline. JAMA 283:1571–1577

    CAS  PubMed  Google Scholar 

  131. Naslund J, Schierhorn A, Hellman U et al (1994) Relative abundance of Alzheimer A beta amyloid peptide variants in Alzheimer disease and normal aging. Proc Natl Acad Sci USA 91:8378–8382

    CAS  PubMed  Google Scholar 

  132. Neumann M, Tolnay M, Mackenzie IR (2009) The molecular basis of frontotemporal dementia. Expert Rev Mol Med 11:e23

    PubMed  Google Scholar 

  133. Nilsberth C, Westlind-Danielsson A, Eckman CB et al (2001) The ‘Arctic’ APP mutation (E693G) causes Alzheimer’s disease by enhanced Abeta protofibril formation. Nat Neurosci 4:887–893

    CAS  PubMed  Google Scholar 

  134. Nishitsuji K, Tomiyama T, Ishibashi K et al (2009) The E693Delta mutation in amyloid precursor protein increases intracellular accumulation of amyloid beta oligomers and causes endoplasmic reticulum stress-induced apoptosis in cultured cells. Am J Pathol 174:957–969

    CAS  PubMed  Google Scholar 

  135. Nixon RA (2007) Autophagy, amyloidogenesis and Alzheimer disease. J Cell Sci 120:4081–4091

    CAS  PubMed  Google Scholar 

  136. Nuntagij P, Oddo S, LaFerla FM, Kotchabhakdi N, Ottersen OP, Torp R (2009) Amyloid deposits show complexity and intimate spatial relationship with dendrosomatic plasma membranes: an electron microscopic 3D reconstruction analysis in 3xTg-AD mice and aged canines. J Alzheimers Dis 16:315–323

    CAS  PubMed  Google Scholar 

  137. Oakley H, Cole SL, Logan S et al (2006) Intraneuronal beta-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer’s disease mutations: potential factors in amyloid plaque formation. J Neurosci 26:10129–10140

    CAS  PubMed  Google Scholar 

  138. Oddo S, Billings L, Kesslak JP, Cribbs DH, LaFerla FM (2004) Abeta immunotherapy leads to clearance of early, but not late, hyperphosphorylated tau aggregates via the proteasome. Neuron 43:321–332

    CAS  PubMed  Google Scholar 

  139. Oddo S, Caccamo A, Smith IF, Green KN, LaFerla FM (2006) A dynamic relationship between intracellular and extracellular pools of Abeta. Am J Pathol 168:184–194

    CAS  PubMed  Google Scholar 

  140. Oddo S, Caccamo A, Shepherd JD et al (2003) Triple-transgenic model of Alzheimer’s disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron 39:409–421

    CAS  PubMed  Google Scholar 

  141. Ohyagi Y, Asahara H, Chui DH et al (2005) Intracellular Abeta42 activates p53 promoter: a pathway to neurodegeneration in Alzheimer’s disease. Faseb J 19:255–257

    CAS  PubMed  Google Scholar 

  142. Palop JJ, Mucke L (2009) Epilepsy and cognitive impairments in Alzheimer disease. Arch Neurol 66:435–440

    PubMed  Google Scholar 

  143. Pastorino L, Sun A, Lu PJ et al (2006) The prolyl isomerase Pin1 regulates amyloid precursor protein processing and amyloid-beta production. Nature 440:528–534

    CAS  PubMed  Google Scholar 

  144. Perry G, Nunomura A, Hirai K, Takeda A, Aliev G, Smith MA (2000) Oxidative damage in Alzheimer’s disease: the metabolic dimension. Int J Dev Neurosci 18:417–421

    CAS  PubMed  Google Scholar 

  145. Philipson O, Lannfelt L, Nilsson LN (2009) Genetic and pharmacological evidence of intraneuronal Abeta accumulation in APP transgenic mice. FEBS Lett 583:3021–3026

    CAS  PubMed  Google Scholar 

  146. Pike CJ, Overman MJ, Cotman CW (1995) Amino-terminal deletions enhance aggregation of beta-amyloid peptides in vitro. J Biol Chem 270:23895–23898

    CAS  PubMed  Google Scholar 

  147. Puzzo D, Privitera L, Leznik E et al (2008) Picomolar amyloid-beta positively modulates synaptic plasticity and memory in hippocampus. J Neurosci 28:14537–14545

    CAS  PubMed  Google Scholar 

  148. Querfurth HW, LaFerla FM (2010) Alzheimer’s disease. N Engl J Med 362:329–344

    CAS  PubMed  Google Scholar 

  149. Reddy PH (2008) Mitochondrial medicine for aging and neurodegenerative diseases. Neuromolecular Med 10:291–315

    CAS  PubMed  Google Scholar 

  150. Reiman EM, Chen K, Alexander GE et al (2004) Functional brain abnormalities in young adults at genetic risk for late-onset Alzheimer’s dementia. Proc Natl Acad Sci USA 101:284–289

    CAS  PubMed  Google Scholar 

  151. Roberson ED, Scearce-Levie K, Palop JJ et al (2007) Reducing endogenous tau ameliorates amyloid beta-induced deficits in an Alzheimer’s disease mouse model. Science 316:750–754

    CAS  PubMed  Google Scholar 

  152. Roberts GW, Gentleman SM, Lynch A, Murray L, Landon M, Graham DI (1994) Beta amyloid protein deposition in the brain after severe head injury: implications for the pathogenesis of Alzheimer’s disease. J Neurol Neurosurg Psychiatry 57:419–425

    CAS  PubMed  Google Scholar 

  153. Rovelet-Lecrux A, Hannequin D, Raux G et al (2006) APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy. Nat Genet 38:24–26

    CAS  PubMed  Google Scholar 

  154. Runz H, Rietdorf J, Tomic I et al (2002) Inhibition of intracellular cholesterol transport alters presenilin localization and amyloid precursor protein processing in neuronal cells. J Neurosci 22:1679–1689

    CAS  PubMed  Google Scholar 

  155. Russo C, Schettini G, Saido TC et al (2000) Presenilin-1 mutations in Alzheimer’s disease. Nature 405:531–532

    CAS  PubMed  Google Scholar 

  156. Saavedra L, Mohamed A, Ma V, Kar S, de Chaves EP (2007) Internalization of beta-amyloid peptide by primary neurons in the absence of apolipoprotein E. J Biol Chem 282:35722–35732

    CAS  PubMed  Google Scholar 

  157. Saido TC, Yamao-Harigaya W, Iwatsubo T, Kawashima S (1996) Amino- and carboxyl-terminal heterogeneity of beta-amyloid peptides deposited in human brain. Neurosci Lett 215:173–176

    CAS  PubMed  Google Scholar 

  158. Saido TC, Iwatsubo T, Mann DM, Shimada H, Ihara Y, Kawashima S (1995) Dominant and differential deposition of distinct beta-amyloid peptide species, A beta N3(pE), in senile plaques. Neuron 14:457–466

    CAS  PubMed  Google Scholar 

  159. Sannerud R, Annaert W (2009) Trafficking, a key player in regulated intramembrane proteolysis. Semin Cell Dev Biol 20:183–190

    CAS  PubMed  Google Scholar 

  160. Santacruz K, Lewis J, Spires T et al (2005) Tau suppression in a neurodegenerative mouse model improves memory function. Science 309:476–481

    CAS  PubMed  Google Scholar 

  161. Sastre M (2010) Troubleshooting methods for APP processing in vitro. J Pharmacol Toxicol Methods. doi:101016/jvascn201002003

  162. Saura CA, Chen G, Malkani S et al (2005) Conditional inactivation of presenilin 1 prevents amyloid accumulation and temporarily rescues contextual and spatial working memory impairments in amyloid precursor protein transgenic mice. J Neurosci 25:6755–6764

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  164. Schenk D, Barbour R, Dunn W et al (1999) Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 400:173–177

    CAS  PubMed  Google Scholar 

  165. Schlenzig D, Manhart S, Cinar Y et al (2009) Pyroglutamate formation influences solubility and amyloidogenicity of amyloid peptides. Biochemistry 48:7072–7078

    CAS  PubMed  Google Scholar 

  166. Schmechel DE, Saunders AM, Strittmatter WJ et al (1993) Increased amyloid beta-peptide deposition in cerebral cortex as a consequence of apolipoprotein E genotype in late-onset Alzheimer disease. Proc Natl Acad Sci USA 90:9649–9653

    CAS  PubMed  Google Scholar 

  167. Schmitz C, Rutten BP, Pielen A et al (2004) Hippocampal neuron loss exceeds amyloid plaque load in a transgenic mouse model of Alzheimer’s disease. Am J Pathol 164:1495–1502

    PubMed  Google Scholar 

  168. Selkoe DJ (2002) Alzheimer’s disease is a synaptic failure. Science 298:789–791

    CAS  PubMed  Google Scholar 

  169. Shaked GM, Kummer MP, Lu DC, Galvan V, Bredesen DE, Koo EH (2006) Abeta induces cell death by direct interaction with its cognate extracellular domain on APP (APP 597–624). Faseb J 20:1254–1256

    CAS  PubMed  Google Scholar 

  170. Shankar GM, Li S, Mehta TH et al (2008) Amyloid-beta protein dimers isolated directly from Alzheimer’s brains impair synaptic plasticity and memory. Nat Med 14:837–842

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  172. Shie FS, LeBoeuf RC, Jin LW (2003) Early intraneuronal Abeta deposition in the hippocampus of APP transgenic mice. Neuroreport 14:123–129

    CAS  PubMed  Google Scholar 

  173. Siman R, Reaume AG, Savage MJ et al (2000) Presenilin-1 P264L knock-in mutation: differential effects on abeta production, amyloid deposition, and neuronal vulnerability. J Neurosci 20:8717–8726

    CAS  PubMed  Google Scholar 

  174. Skovronsky DM, Doms RW, Lee VM (1998) Detection of a novel intraneuronal pool of insoluble amyloid beta protein that accumulates with time in culture. J Cell Biol 141:1031–1039

    CAS  PubMed  Google Scholar 

  175. Small SA, Gandy S (2006) Sorting through the cell biology of Alzheimer’s disease: intracellular pathways to pathogenesis. Neuron 52:15–31

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  177. Snyder EM, Nong Y, Almeida CG et al (2005) Regulation of NMDA receptor trafficking by amyloid-beta. Nat Neurosci 8:1051–1058

    CAS  PubMed  Google Scholar 

  178. Solomon B (2007) Clinical immunologic approaches for the treatment of Alzheimer’s disease. Expert Opin Investig Drugs 16:819–828

    CAS  PubMed  Google Scholar 

  179. Sperling RA, Laviolette PS, O’Keefe K et al (2009) Amyloid deposition is associated with impaired default network function in older persons without dementia. Neuron 63:178–188

    CAS  PubMed  Google Scholar 

  180. Steinerman JR, Irizarry M, Scarmeas N et al (2008) Distinct pools of beta-amyloid in Alzheimer disease-affected brain: a clinicopathologic study. Arch Neurol 65:906–912

    PubMed  Google Scholar 

  181. Stenh C, Englund H, Lord A et al (2005) Amyloid-beta oligomers are inefficiently measured by enzyme-linked immunosorbent assay. Ann Neurol 58:147–150

    CAS  PubMed  Google Scholar 

  182. Stokin GB, Lillo C, Falzone TL et al (2005) Axonopathy and transport deficits early in the pathogenesis of Alzheimer’s disease. Science 307:1282–1288

    CAS  PubMed  Google Scholar 

  183. Sultana R, Butterfield DA (2010) Role of oxidative stress in the progression of Alzheimer’s disease. J Alzheimers Dis 19:341–353

    PubMed  Google Scholar 

  184. 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 56:933–944

    CAS  PubMed  Google Scholar 

  185. Tabira T, Chui DH, Kuroda S (2002) Significance of intracellular Abeta42 accumulation in Alzheimer’s disease. Front Biosci 7:a44–a49

    CAS  PubMed  Google Scholar 

  186. 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. doi:101016/jneurobiolaging200807021

  187. Takahashi RH, Almeida CG, Kearney PF et al (2004) Oligomerization of Alzheimer’s beta-amyloid within processes and synapses of cultured neurons and brain. J Neurosci 24:3592–3599

    CAS  PubMed  Google Scholar 

  188. Takahashi RH, Milner TA, Li F et al (2002) Intraneuronal Alzheimer abeta42 accumulates in multivesicular bodies and is associated with synaptic pathology. Am J Pathol 161:1869–1879

    CAS  PubMed  Google Scholar 

  189. Tampellini D, Magrane J, Takahashi RH et al (2007) Internalized antibodies to the Abeta domain of APP reduce neuronal Abeta and protect against synaptic alterations. J Biol Chem 282:18895–18906

    CAS  PubMed  Google Scholar 

  190. Tampellini D, Rahman N, Gallo EF et al (2009) Synaptic activity reduces intraneuronal Abeta, promotes APP transport to synapses, and protects against Abeta-related synaptic alterations. J Neurosci 29:9704–9713

    CAS  PubMed  Google Scholar 

  191. Teller JK, Russo C, DeBusk LM et al (1996) Presence of soluble amyloid beta-peptide precedes amyloid plaque formation in Down’s syndrome. Nat Med 2:93–95

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  193. Thal DR, Del Tredici K, Braak H (2004) Neurodegeneration in normal brain aging and disease. Sci Aging Knowl Environ 9:pe26

    Google Scholar 

  194. Thinakaran G, Koo EH (2008) Amyloid precursor protein trafficking, processing, and function. J Biol Chem 283:29615–29619

    CAS  PubMed  Google Scholar 

  195. Turner RS, Suzuki N, Chyung AS, Younkin SG, Lee VM (1996) Amyloids beta40 and beta42 are generated intracellularly in cultured human neurons and their secretion increases with maturation. J Biol Chem 271:8966–8970

    CAS  PubMed  Google Scholar 

  196. Van Broeck B, Vanhoutte G, Pirici D et al (2008) Intraneuronal amyloid beta and reduced brain volume in a novel APP T714I mouse model for Alzheimer’s disease. Neurobiol Aging 29:241–252

    PubMed  Google Scholar 

  197. Vassar R, Bennett BD, Babu-Khan S et al (1999) Beta-secretase cleavage of Alzheimer’s amyloid precursor protein by the transmembrane aspartic protease BACE. Science 286:735–741

    CAS  PubMed  Google Scholar 

  198. Walsh DM, Klyubin I, Fadeeva JV et al (2002) Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature 416:535–539

    CAS  PubMed  Google Scholar 

  199. Wang Z, Wang B, Yang L et al (2009) Presynaptic and postsynaptic interaction of the amyloid precursor protein promotes peripheral and central synaptogenesis. J Neurosci 29:10788–10801

    CAS  PubMed  Google Scholar 

  200. Weller RO, Djuanda E, Yow HY, Carare RO (2009) Lymphatic drainage of the brain and the pathophysiology of neurological disease. Acta Neuropathol 117:1–14

    CAS  PubMed  Google Scholar 

  201. Wertkin AM, Turner RS, Pleasure SJ et al (1993) Human neurons derived from a teratocarcinoma cell line express solely the 695-amino acid amyloid precursor protein and produce intracellular beta-amyloid or A4 peptides. Proc Natl Acad Sci USA 90:9513–9517

    CAS  PubMed  Google Scholar 

  202. Wild-Bode C, Yamazaki T, Capell A et al (1997) Intracellular generation and accumulation of amyloid beta-peptide terminating at amino acid 42. J Biol Chem 272:16085–16088

    CAS  PubMed  Google Scholar 

  203. Wilson CA, Doms RW, Lee VM (1999) Intracellular APP processing and A beta production in Alzheimer disease. J Neuropathol Exp Neurol 58:787–794

    CAS  PubMed  Google Scholar 

  204. Wirths O, Multhaup G, Bayer TA (2004) A modified beta-amyloid hypothesis: intraneuronal accumulation of the beta-amyloid peptide—the first step of a fatal cascade. J Neurochem 91:513–520

    CAS  PubMed  Google Scholar 

  205. Wirths O, Multhaup G, Czech C et al (2001) Intraneuronal Abeta accumulation precedes plaque formation in beta-amyloid precursor protein and presenilin-1 double-transgenic mice. Neurosci Lett 306:116–120

    CAS  PubMed  Google Scholar 

  206. Wirths O, Bethge T, Marcello A et al (2010) Pyroglutamate Abeta pathology in APP/PS1KI mice, sporadic and familial Alzheimer’s disease cases. J Neural Transm 117:85–96

    CAS  PubMed  Google Scholar 

  207. WorkingGroup (1997) Consensus recommendations for the postmortem diagnosis of Alzheimer’s disease. The National Institute on aging, and Reagan Institute Working Group on Diagnostic Criteria for the Neuropathological Assessment of Alzheimer’s Disease. Neurobiol Aging 18:S1–S2

    Google Scholar 

  208. Wyss-Coray T, Mucke L (2002) Inflammation in neurodegenerative disease—a double-edged sword. Neuron 35:419–432

    CAS  PubMed  Google Scholar 

  209. Yamaguchi H, Maat-Schieman ML, van Duinen SG et al (2000) Amyloid beta protein (Abeta) starts to deposit as plasma membrane-bound form in diffuse plaques of brains from hereditary cerebral hemorrhage with amyloidosis-Dutch type, Alzheimer disease and nondemented aged subjects. J Neuropathol Exp Neurol 59:723–732

    CAS  PubMed  Google Scholar 

  210. Yang AJ, Knauer M, Burdick DA, Glabe C (1995) Intracellular A beta 1-42 aggregates stimulate the accumulation of stable, insoluble amyloidogenic fragments of the amyloid precursor protein in transfected cells. J Biol Chem 270:14786–14792

    CAS  PubMed  Google Scholar 

  211. Yang AJ, Chandswangbhuvana D, Shu T, Henschen A, Glabe CG (1999) Intracellular accumulation of insoluble, newly synthesized abeta n-42 in amyloid precursor protein-transfected cells that have been treated with Abeta1-42. J Biol Chem 274:20650–20656

    CAS  PubMed  Google Scholar 

  212. Yang L, Wang Z, Wang B, Justice NJ, Zheng H (2009) Amyloid precursor protein regulates Cav1.2 L-type calcium channel levels and function to influence GABAergic short-term plasticity. J Neurosci 29:15660–15668

    CAS  PubMed  Google Scholar 

  213. Zhang Y, McLaughlin R, Goodyer C, LeBlanc A (2002) Selective cytotoxicity of intracellular amyloid beta peptide1-42 through p53 and Bax in cultured primary human neurons. J Cell Biol 156:519–529

    CAS  PubMed  Google Scholar 

  214. Zheng H, Jiang M, Trumbauer ME et al (1995) beta-Amyloid precursor protein-deficient mice show reactive gliosis and decreased locomotor activity. Cell 81:525–531

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The support of National Institutes of Health grants AG028174 and AG027140, and Alzheimer’s Association New Investigator award (D.T.) and Zenith award (G.K.G.). We thank Xun (Julie) Lian for helpful technical assistance.

Conflict of interest statement

The authors declare that they have no commercial or financial relationship that could be construed as a potential conflict of interest.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Gunnar K. Gouras.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gouras, G.K., Tampellini, D., Takahashi, R.H. et al. Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease. Acta Neuropathol 119, 523–541 (2010). https://doi.org/10.1007/s00401-010-0679-9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00401-010-0679-9

Keywords

Navigation