Acta Neuropathologica

, Volume 119, Issue 5, pp 523–541 | Cite as

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

  • Gunnar K. Gouras
  • Davide Tampellini
  • Reisuke H. Takahashi
  • Estibaliz Capetillo-Zarate
Review

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.

Keywords

Amyloid Synapse Tau Head injury Endosome Dementia pugilistica 

References

  1. 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 115:533–546PubMedGoogle Scholar
  2. 2.
    Almeida CG, Takahashi RH, Gouras GK (2006) Beta-amyloid accumulation impairs multivesicular body sorting by inhibiting the ubiquitin-proteasome system. J Neurosci 26:4277–4288PubMedGoogle Scholar
  3. 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 20:187–198PubMedGoogle Scholar
  4. 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 136:255–260PubMedGoogle Scholar
  5. 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 19:1085–1089PubMedGoogle Scholar
  6. 6.
    Arendt T (2009) Synaptic degeneration in Alzheimer’s disease. Acta Neuropathol 118:167–179PubMedGoogle Scholar
  7. 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 10:125–132PubMedGoogle Scholar
  8. 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 6:916–919PubMedGoogle Scholar
  9. 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. 10.
    Bence NF, Sampat RM, Kopito RR (2001) Impairment of the ubiquitin-proteasome system by protein aggregation. Science 292:1552–1555PubMedGoogle Scholar
  11. 11.
    Bertram L, Tanzi RE (2008) Thirty years of Alzheimer’s disease genetics: the implications of systematic meta-analyses. Nat Rev Neurosci 9:768–778PubMedGoogle Scholar
  12. 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 45:675–688PubMedGoogle Scholar
  13. 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 29:10405–10409PubMedGoogle Scholar
  14. 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 184:247–263PubMedGoogle Scholar
  15. 15.
    Blennow K, Hampel H, Weiner M, Zetterberg H (2010) Cerebrospinal fluid and plasma biomarkers in Alzheimer disease. Nat Rev Neurol 6:131–144PubMedGoogle Scholar
  16. 16.
    Brody DL, Magnoni S, Schwetye KE et al (2008) Amyloid-beta dynamics correlate with neurological status in the injured human brain. Science 321:1221–1224PubMedGoogle Scholar
  17. 17.
    Bu G (2009) Apolipoprotein E and its receptors in Alzheimer’s disease: pathways, pathogenesis and therapy. Nat Rev Neurosci 10:333–344PubMedGoogle Scholar
  18. 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 25:7709–7717PubMedGoogle Scholar
  19. 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 33:677–688PubMedGoogle Scholar
  20. 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 26:645–654PubMedGoogle Scholar
  21. 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 4:233–234PubMedGoogle Scholar
  22. 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 129:2992–3005PubMedGoogle Scholar
  23. 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 165:1289–1300PubMedGoogle Scholar
  24. 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 25:1263–1272PubMedGoogle Scholar
  25. 25.
    Cirrito JR, Kang JE, Lee J et al (2008) Endocytosis is required for synaptic activity-dependent release of amyloid-beta in vivo. Neuron 58:42–51PubMedGoogle Scholar
  26. 26.
    Cirrito JR, Yamada KA, Finn MB et al (2005) Synaptic activity regulates interstitial fluid amyloid-beta levels in vivo. Neuron 48:913–922PubMedGoogle Scholar
  27. 27.
    Clinton J, Ambler MW, Roberts GW (1991) Post-traumatic Alzheimer’s disease: preponderance of a single plaque type. Neuropathol Appl Neurobiol 17:69–74PubMedGoogle Scholar
  28. 28.
    Coleman PD, Yao PJ (2003) Synaptic slaughter in Alzheimer’s disease. Neurobiol Aging 24:1023–1027PubMedGoogle Scholar
  29. 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 22:2215–2224PubMedGoogle Scholar
  30. 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 261:921–923PubMedGoogle Scholar
  31. 31.
    Corsellis JA, Bruton CJ, Freeman-Browne D (1973) The aftermath of boxing. Psychol Med 3:270–303PubMedGoogle Scholar
  32. 32.
    Chapman PF, White GL, Jones MW et al (1999) Impaired synaptic plasticity and learning in aged amyloid precursor protein transgenic mice. Nat Neurosci 2:271–276PubMedGoogle Scholar
  33. 33.
    Chen X, Yan SD (2006) Mitochondrial Abeta: a potential cause of metabolic dysfunction in Alzheimer’s disease. IUBMB Life 58:686–694PubMedGoogle Scholar
  34. 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 1301:116–125PubMedGoogle Scholar
  35. 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 116:647–655PubMedGoogle Scholar
  36. 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 5:560–564PubMedGoogle Scholar
  37. 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. 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 38:120–134PubMedGoogle Scholar
  39. 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 342:114–118PubMedGoogle Scholar
  40. 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 78:151–164PubMedGoogle Scholar
  41. 41.
    De Strooper B, Vassar R, Golde T (2010) The secretases: enzymes with therapeutic potential in Alzheimer disease. Nat Rev Neurol 6:99–107PubMedGoogle Scholar
  42. 42.
    DeKosky ST, Scheff SW (1990) Synapse loss in frontal cortex biopsies in Alzheimer’s disease: correlation with cognitive severity. Ann Neurol 27:457–464PubMedGoogle Scholar
  43. 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 29:4004–4015PubMedGoogle Scholar
  44. 44.
    Duyckaerts C, Delatour B, Potier MC (2009) Classification and basic pathology of Alzheimer disease. Acta Neuropathol 118:5–36PubMedGoogle Scholar
  45. 45.
    Echeverria V, Cuello AC (2002) Intracellular A-beta amyloid, a sign for worse things to come? Mol Neurobiol 26:299–316PubMedGoogle Scholar
  46. 46.
    Ehlers MD (2003) Activity level controls postsynaptic composition and signaling via the ubiquitin-proteasome system. Nat Neurosci 6:231–242PubMedGoogle Scholar
  47. 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 67:513–521PubMedGoogle Scholar
  48. 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 65:176–183PubMedGoogle Scholar
  49. 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 107:1942–1947PubMedGoogle Scholar
  50. 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 43:39–56PubMedGoogle Scholar
  51. 51.
    Glabe C (2001) Intracellular mechanisms of amyloid accumulation and pathogenesis in Alzheimer’s disease. J Mol Neurosci 17:137–145PubMedGoogle Scholar
  52. 52.
    Goate AM, Haynes AR, Owen MJ et al (1989) Predisposing locus for Alzheimer’s disease on chromosome 21. Lancet 1:352–355PubMedGoogle Scholar
  53. 53.
    Golde TE, Das P, Levites Y (2009) Quantitative and mechanistic studies of Abeta immunotherapy. CNS Neurol Disord Drug Targets 8:31–49PubMedGoogle Scholar
  54. 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 7:873–888PubMedGoogle Scholar
  55. 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 191:43–48PubMedGoogle Scholar
  56. 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 293:1491–1495PubMedGoogle Scholar
  57. 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 155–160Google Scholar
  58. 58.
    Gouras GK, Almeida CG, Takahashi RH (2005) Intraneuronal Abeta accumulation and origin of plaques in Alzheimer’s disease. Neurobiol Aging 26:1235–1244PubMedGoogle Scholar
  59. 59.
    Gouras GK, Xu H, Jovanovic JN et al (1998) Generation and regulation of beta-amyloid peptide variants by neurons. J Neurochem 71:1920–1925PubMedCrossRefGoogle Scholar
  60. 60.
    Gouras GK, Tsai J, Naslund J et al (2000) Intraneuronal Abeta42 accumulation in human brain. Am J Pathol 156:15–20PubMedGoogle Scholar
  61. 61.
    Grinberg LT, Thal DR (2010) Vascular pathology in the aged human brain. Acta Neuropathol 119:277–290PubMedGoogle Scholar
  62. 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 86:2853–2857PubMedGoogle Scholar
  63. 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 165:1809–1817PubMedGoogle Scholar
  64. 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 125:489–492PubMedGoogle Scholar
  65. 65.
    Haass C, Selkoe DJ (2007) Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer’s amyloid beta-peptide. Nat Rev Mol Cell Biol 8:101–112PubMedGoogle Scholar
  66. 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 9:705–710PubMedGoogle Scholar
  67. 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 105:13145–13150PubMedGoogle Scholar
  68. 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 276:422–427PubMedGoogle Scholar
  69. 69.
    Hartmann T (1999) Intracellular biology of Alzheimer’s disease amyloid beta peptide. Eur Arch Psychiatry Clin Neurosci 249:291–298PubMedGoogle Scholar
  70. 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. 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 17:205–218PubMedGoogle Scholar
  72. 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 26:1343–1354PubMedGoogle Scholar
  73. 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 7:954–960PubMedGoogle Scholar
  74. 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 4:97–100PubMedGoogle Scholar
  75. 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 372:216–223PubMedGoogle Scholar
  76. 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 319:733–737PubMedGoogle Scholar
  77. 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 96:3228–3233PubMedGoogle Scholar
  78. 78.
    Hsiao K, Chapman P, Nilsen S et al (1996) Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice. Science 274:99–102PubMedGoogle Scholar
  79. 79.
    Hsieh H, Boehm J, Sato C et al (2006) AMPAR removal underlies Abeta-induced synaptic depression and dendritic spine loss. Neuron 52:831–843PubMedGoogle Scholar
  80. 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 101:352–355PubMedGoogle Scholar
  81. 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 6:143–150PubMedGoogle Scholar
  82. 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 13:45–53PubMedGoogle Scholar
  83. 83.
    Jack CR Jr, Knopman DS, Jagust WJ et al (2010) Hypothetical model of dynamic biomarkers of the Alzheimer’s pathological cascade. Lancet Neurol 9:119–128PubMedGoogle Scholar
  84. 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 164:975–985PubMedGoogle Scholar
  85. 85.
    Kamenetz F, Tomita T, Hsieh H et al (2003) APP processing and synaptic function. Neuron 37:925–937PubMedGoogle Scholar
  86. 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 21:372–381PubMedGoogle Scholar
  87. 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 2:18PubMedGoogle Scholar
  88. 88.
    Kim J, Basak JM, Holtzman DM (2009) The role of apolipoprotein E in Alzheimer’s disease. Neuron 63:287–303PubMedGoogle Scholar
  89. 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 28:1297–1306PubMedGoogle Scholar
  90. 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 9:2589–2598PubMedGoogle Scholar
  91. 91.
    Lacor PN, Buniel MC, Chang L et al (2004) Synaptic targeting by Alzheimer’s-related amyloid beta oligomers. J Neurosci 24:10191–10200PubMedGoogle Scholar
  92. 92.
    LaFerla FM, Green KN, Oddo S (2007) Intracellular amyloid-beta in Alzheimer’s disease. Nat Rev Neurosci 8:499–509PubMedGoogle Scholar
  93. 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 9:21–30PubMedGoogle Scholar
  94. 94.
    Lah JJ, Heilman CJ, Nash NR et al (1997) Light and electron microscopic localization of presenilin-1 in primate brain. J Neurosci 17:1971–1980PubMedGoogle Scholar
  95. 95.
    Langui D, Girardot N, El Hachimi KH et al (2004) Subcellular topography of neuronal Abeta peptide in APPxPS1 transgenic mice. Am J Pathol 165:1465–1477PubMedGoogle Scholar
  96. 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 22:9785–9793PubMedGoogle Scholar
  97. 97.
    Lazarov O, Robinson J, Tang YP et al (2005) Environmental enrichment reduces Abeta levels and amyloid deposition in transgenic mice. Cell 120:701–713PubMedGoogle Scholar
  98. 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 3:16–32PubMedGoogle Scholar
  99. 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. 100.
    Lesne S, Koh MT, Kotilinek L et al (2006) A specific amyloid-beta protein assembly in the brain impairs memory. Nature 440:352–357PubMedGoogle Scholar
  101. 101.
    Lewis J, Dickson DW, Lin WL et al (2001) Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP. Science 293:1487–1491PubMedGoogle Scholar
  102. 102.
    Li F, Calingasan NY, Yu F et al (2004) Increased plaque burden in brains of APP mutant MnSOD heterozygous knockout mice. J Neurochem 89:1308–1312PubMedGoogle Scholar
  103. 103.
    Lin MT, Beal MF (2006) Alzheimer’s APP mangles mitochondria. Nat Med 12:1241–1243PubMedGoogle Scholar
  104. 104.
    Lin MT, Beal MF (2006) Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443:787–795PubMedGoogle Scholar
  105. 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 156:843–854PubMedGoogle Scholar
  106. 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 27:67–77PubMedGoogle Scholar
  107. 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 3:460–464PubMedGoogle Scholar
  108. 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 155:853–862PubMedGoogle Scholar
  109. 109.
    Lustbader JW, Cirilli M, Lin C et al (2004) ABAD directly links Abeta to mitochondrial toxicity in Alzheimer’s disease. Science 304:448–452PubMedGoogle Scholar
  110. 110.
    Mackenzie IR, Miller LA (1994) Senile plaques in temporal lobe epilepsy. Acta Neuropathol 87:504–510PubMedGoogle Scholar
  111. 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–S188PubMedGoogle Scholar
  112. 112.
    Masliah E, Crews L, Hansen L (2006) Synaptic remodeling during aging and in Alzheimer’s disease. J Alzheimers Dis 9:91–99PubMedGoogle Scholar
  113. 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 174:67–72PubMedGoogle Scholar
  114. 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 16:5795–5811PubMedGoogle Scholar
  115. 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 4:2757–2763PubMedGoogle Scholar
  116. 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 33:494–501PubMedGoogle Scholar
  117. 117.
    McGowan E, Pickford F, Kim J et al (2005) Abeta42 is essential for parenchymal and vascular amyloid deposition in mice. Neuron 47:191–199PubMedGoogle Scholar
  118. 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 46:860–866PubMedGoogle Scholar
  119. 119.
    Mesulam MM (1999) Neuroplasticity failure in Alzheimer’s disease: bridging the gap between plaques and tangles. Neuron 24:521–529PubMedGoogle Scholar
  120. 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 451:720–724PubMedGoogle Scholar
  121. 121.
    Meyer-Luehmann M, Coomaraswamy J, Bolmont T et al (2006) Exogenous induction of cerebral beta-amyloidogenesis is governed by agent and host. Science 313:1781–1784PubMedGoogle Scholar
  122. 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 105:2181–2186PubMedGoogle Scholar
  123. 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 355:42–43PubMedGoogle Scholar
  124. 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 274:6483–6492PubMedGoogle Scholar
  125. 125.
    Moolman DL, Vitolo OV, Vonsattel JP, Shelanski ML (2004) Dendrite and dendritic spine alterations in Alzheimer models. J Neurocytol 33:377–387PubMedGoogle Scholar
  126. 126.
    Mori C, Spooner ET, Wisniewsk KE et al (2002) Intraneuronal Abeta42 accumulation in Down syndrome brain. Amyloid 9:88–102PubMedGoogle Scholar
  127. 127.
    Mortimer JA, French LR, Hutton JT, Schuman LM (1985) Head injury as a risk factor for Alzheimer’s disease. Neurology 35:264–267PubMedGoogle Scholar
  128. 128.
    Mrak RE, Griffin WS (2001) Interleukin-1, neuroinflammation, and Alzheimer’s disease. Neurobiol Aging 22:903–908PubMedGoogle Scholar
  129. 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 29:3565–3578PubMedGoogle Scholar
  130. 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 283:1571–1577PubMedGoogle Scholar
  131. 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 91:8378–8382PubMedGoogle Scholar
  132. 132.
    Neumann M, Tolnay M, Mackenzie IR (2009) The molecular basis of frontotemporal dementia. Expert Rev Mol Med 11:e23PubMedGoogle Scholar
  133. 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 4:887–893PubMedGoogle Scholar
  134. 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 174:957–969PubMedGoogle Scholar
  135. 135.
    Nixon RA (2007) Autophagy, amyloidogenesis and Alzheimer disease. J Cell Sci 120:4081–4091PubMedGoogle Scholar
  136. 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 16:315–323PubMedGoogle Scholar
  137. 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 26:10129–10140PubMedGoogle Scholar
  138. 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 43:321–332PubMedGoogle Scholar
  139. 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 168:184–194PubMedGoogle Scholar
  140. 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 39:409–421PubMedGoogle Scholar
  141. 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 19:255–257PubMedGoogle Scholar
  142. 142.
    Palop JJ, Mucke L (2009) Epilepsy and cognitive impairments in Alzheimer disease. Arch Neurol 66:435–440PubMedGoogle Scholar
  143. 143.
    Pastorino L, Sun A, Lu PJ et al (2006) The prolyl isomerase Pin1 regulates amyloid precursor protein processing and amyloid-beta production. Nature 440:528–534PubMedGoogle Scholar
  144. 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 18:417–421PubMedGoogle Scholar
  145. 145.
    Philipson O, Lannfelt L, Nilsson LN (2009) Genetic and pharmacological evidence of intraneuronal Abeta accumulation in APP transgenic mice. FEBS Lett 583:3021–3026PubMedGoogle Scholar
  146. 146.
    Pike CJ, Overman MJ, Cotman CW (1995) Amino-terminal deletions enhance aggregation of beta-amyloid peptides in vitro. J Biol Chem 270:23895–23898PubMedGoogle Scholar
  147. 147.
    Puzzo D, Privitera L, Leznik E et al (2008) Picomolar amyloid-beta positively modulates synaptic plasticity and memory in hippocampus. J Neurosci 28:14537–14545PubMedGoogle Scholar
  148. 148.
    Querfurth HW, LaFerla FM (2010) Alzheimer’s disease. N Engl J Med 362:329–344PubMedGoogle Scholar
  149. 149.
    Reddy PH (2008) Mitochondrial medicine for aging and neurodegenerative diseases. Neuromolecular Med 10:291–315PubMedGoogle Scholar
  150. 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 101:284–289PubMedGoogle Scholar
  151. 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 316:750–754PubMedGoogle Scholar
  152. 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 57:419–425PubMedGoogle Scholar
  153. 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 38:24–26PubMedGoogle Scholar
  154. 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 22:1679–1689PubMedGoogle Scholar
  155. 155.
    Russo C, Schettini G, Saido TC et al (2000) Presenilin-1 mutations in Alzheimer’s disease. Nature 405:531–532PubMedGoogle Scholar
  156. 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 282:35722–35732PubMedGoogle Scholar
  157. 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 215:173–176PubMedGoogle Scholar
  158. 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 14:457–466PubMedGoogle Scholar
  159. 159.
    Sannerud R, Annaert W (2009) Trafficking, a key player in regulated intramembrane proteolysis. Semin Cell Dev Biol 20:183–190PubMedGoogle Scholar
  160. 160.
    Santacruz K, Lewis J, Spires T et al (2005) Tau suppression in a neurodegenerative mouse model improves memory function. Science 309:476–481PubMedGoogle Scholar
  161. 161.
    Sastre M (2010) Troubleshooting methods for APP processing in vitro. J Pharmacol Toxicol Methods. doi:101016/jvascn201002003
  162. 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 25:6755–6764PubMedGoogle Scholar
  163. 163.
    Scheff SW, Price DA (2003) Synaptic pathology in Alzheimer’s disease: a review of ultrastructural studies. Neurobiol Aging 24:1029–1046PubMedGoogle Scholar
  164. 164.
    Schenk D, Barbour R, Dunn W et al (1999) Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 400:173–177PubMedGoogle Scholar
  165. 165.
    Schlenzig D, Manhart S, Cinar Y et al (2009) Pyroglutamate formation influences solubility and amyloidogenicity of amyloid peptides. Biochemistry 48:7072–7078PubMedGoogle Scholar
  166. 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 90:9649–9653PubMedGoogle Scholar
  167. 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 164:1495–1502PubMedGoogle Scholar
  168. 168.
    Selkoe DJ (2002) Alzheimer’s disease is a synaptic failure. Science 298:789–791PubMedGoogle Scholar
  169. 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 20:1254–1256PubMedGoogle Scholar
  170. 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 14:837–842PubMedGoogle Scholar
  171. 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 22:9794–9799PubMedGoogle Scholar
  172. 172.
    Shie FS, LeBoeuf RC, Jin LW (2003) Early intraneuronal Abeta deposition in the hippocampus of APP transgenic mice. Neuroreport 14:123–129PubMedGoogle Scholar
  173. 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 20:8717–8726PubMedGoogle Scholar
  174. 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 141:1031–1039PubMedGoogle Scholar
  175. 175.
    Small SA, Gandy S (2006) Sorting through the cell biology of Alzheimer’s disease: intracellular pathways to pathogenesis. Neuron 52:15–31PubMedGoogle Scholar
  176. 176.
    Small SA, Duff K (2008) Linking Abeta and tau in late-onset Alzheimer’s disease: a dual pathway hypothesis. Neuron 60:534–542PubMedGoogle Scholar
  177. 177.
    Snyder EM, Nong Y, Almeida CG et al (2005) Regulation of NMDA receptor trafficking by amyloid-beta. Nat Neurosci 8:1051–1058PubMedGoogle Scholar
  178. 178.
    Solomon B (2007) Clinical immunologic approaches for the treatment of Alzheimer’s disease. Expert Opin Investig Drugs 16:819–828PubMedGoogle Scholar
  179. 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 63:178–188PubMedGoogle Scholar
  180. 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 65:906–912PubMedGoogle Scholar
  181. 181.
    Stenh C, Englund H, Lord A et al (2005) Amyloid-beta oligomers are inefficiently measured by enzyme-linked immunosorbent assay. Ann Neurol 58:147–150PubMedGoogle Scholar
  182. 182.
    Stokin GB, Lillo C, Falzone TL et al (2005) Axonopathy and transport deficits early in the pathogenesis of Alzheimer’s disease. Science 307:1282–1288PubMedGoogle Scholar
  183. 183.
    Sultana R, Butterfield DA (2010) Role of oxidative stress in the progression of Alzheimer’s disease. J Alzheimers Dis 19:341–353PubMedGoogle Scholar
  184. 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 56:933–944PubMedGoogle Scholar
  185. 185.
    Tabira T, Chui DH, Kuroda S (2002) Significance of intracellular Abeta42 accumulation in Alzheimer’s disease. Front Biosci 7:a44–a49PubMedGoogle Scholar
  186. 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. 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 24:3592–3599PubMedGoogle Scholar
  188. 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 161:1869–1879PubMedGoogle Scholar
  189. 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 282:18895–18906PubMedGoogle Scholar
  190. 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 29:9704–9713PubMedGoogle Scholar
  191. 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 2:93–95PubMedGoogle Scholar
  192. 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 30:572–580PubMedGoogle Scholar
  193. 193.
    Thal DR, Del Tredici K, Braak H (2004) Neurodegeneration in normal brain aging and disease. Sci Aging Knowl Environ 9:pe26Google Scholar
  194. 194.
    Thinakaran G, Koo EH (2008) Amyloid precursor protein trafficking, processing, and function. J Biol Chem 283:29615–29619PubMedGoogle Scholar
  195. 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 271:8966–8970PubMedGoogle Scholar
  196. 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 29:241–252PubMedGoogle Scholar
  197. 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 286:735–741PubMedGoogle Scholar
  198. 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 416:535–539PubMedGoogle Scholar
  199. 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 29:10788–10801PubMedGoogle Scholar
  200. 200.
    Weller RO, Djuanda E, Yow HY, Carare RO (2009) Lymphatic drainage of the brain and the pathophysiology of neurological disease. Acta Neuropathol 117:1–14PubMedGoogle Scholar
  201. 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 90:9513–9517PubMedGoogle Scholar
  202. 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 272:16085–16088PubMedGoogle Scholar
  203. 203.
    Wilson CA, Doms RW, Lee VM (1999) Intracellular APP processing and A beta production in Alzheimer disease. J Neuropathol Exp Neurol 58:787–794PubMedGoogle Scholar
  204. 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 91:513–520PubMedGoogle Scholar
  205. 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 306:116–120PubMedGoogle Scholar
  206. 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 117:85–96PubMedGoogle Scholar
  207. 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–S2Google Scholar
  208. 208.
    Wyss-Coray T, Mucke L (2002) Inflammation in neurodegenerative disease—a double-edged sword. Neuron 35:419–432PubMedGoogle Scholar
  209. 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 59:723–732PubMedGoogle Scholar
  210. 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 270:14786–14792PubMedGoogle Scholar
  211. 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 274:20650–20656PubMedGoogle Scholar
  212. 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 29:15660–15668PubMedGoogle Scholar
  213. 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 156:519–529PubMedGoogle Scholar
  214. 214.
    Zheng H, Jiang M, Trumbauer ME et al (1995) beta-Amyloid precursor protein-deficient mice show reactive gliosis and decreased locomotor activity. Cell 81:525–531PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Gunnar K. Gouras
    • 1
  • Davide Tampellini
    • 1
  • Reisuke H. Takahashi
    • 2
  • Estibaliz Capetillo-Zarate
    • 1
  1. 1.Department for Neurology and NeuroscienceWeill Cornell Medical CollegeNew YorkUSA
  2. 2.Department of PathologyTokyo Medical University HospitalTokyoJapan

Personalised recommendations