nach oben

Acta Neuropathologica

Erschienen in:

01.05.2010 | Review

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

verfasst von: Gunnar K. Gouras, Davide Tampellini, Reisuke H. Takahashi, Estibaliz Capetillo-Zarate

Erschienen in: Acta Neuropathologica | Ausgabe 5/2010

Einloggen, um Zugang zu erhalten

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.

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 115:533–546PubMed

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

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 20:187–198PubMed

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 136:255–260PubMed

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 19:1085–1089PubMed

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

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 10:125–132PubMed

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 6:916–919PubMed

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

10.

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

11.

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

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 45:675–688PubMed

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 29:10405–10409PubMed

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 184:247–263PubMed

15.

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

16.

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

17.

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

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 25:7709–7717PubMed

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 33:677–688PubMed

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 26:645–654PubMed

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 4:233–234PubMed

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 129:2992–3005PubMed

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 165:1289–1300PubMed

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 25:1263–1272PubMed

25.

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

26.

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

27.

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

28.

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

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 22:2215–2224PubMed

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 261:921–923PubMed

31.

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

32.

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

33.

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

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 1301:116–125PubMed

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 116:647–655PubMed

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 5:560–564PubMed

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 38:120–134PubMed

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 342:114–118PubMed

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 78:151–164PubMed

41.

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

42.

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

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 29:4004–4015PubMed

44.

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

45.

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

46.

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

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 67:513–521PubMed

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 65:176–183PubMed

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 107:1942–1947PubMed

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 43:39–56PubMed

51.

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

52.

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

53.

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

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 7:873–888PubMed

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 191:43–48PubMed

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 293:1491–1495PubMed

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

58.

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

59.

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

60.

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

61.

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

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 86:2853–2857PubMed

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 165:1809–1817PubMed

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 125:489–492PubMed

65.

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

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 9:705–710PubMed

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 105:13145–13150PubMed

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 276:422–427PubMed

69.

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

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 17:205–218PubMed

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 26:1343–1354PubMed

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 7:954–960PubMed

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 4:97–100PubMed

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 372:216–223PubMed

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 319:733–737PubMed

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 96:3228–3233PubMed

78.

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

79.

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

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 101:352–355PubMed

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 6:143–150PubMed

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 13:45–53PubMed

83.

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

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 164:975–985PubMed

85.

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

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 21:372–381PubMed

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 2:18PubMed

88.

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

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 28:1297–1306PubMed

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 9:2589–2598PubMed

91.

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

92.

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

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 9:21–30PubMed

94.

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

95.

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

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 22:9785–9793PubMed

97.

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

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 3:16–32PubMed

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 440:352–357PubMed

101.

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

102.

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

103.

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

104.

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

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 156:843–854PubMed

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 27:67–77PubMed

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 3:460–464PubMed

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 155:853–862PubMed

109.

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

110.

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

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–S188PubMed

112.

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

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 174:67–72PubMed

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 16:5795–5811PubMed

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 4:2757–2763PubMed

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 33:494–501PubMed

117.

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

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 46:860–866PubMed

119.

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

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 451:720–724PubMed

121.

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

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 105:2181–2186PubMed

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 355:42–43PubMed

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 274:6483–6492PubMed

125.

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

126.

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

127.

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

128.

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

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 29:3565–3578PubMed

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 283:1571–1577PubMed

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 91:8378–8382PubMed

132.

Neumann M, Tolnay M, Mackenzie IR (2009) The molecular basis of frontotemporal dementia. Expert Rev Mol Med 11:e23PubMed

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 4:887–893PubMed

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 174:957–969PubMed

135.

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

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 16:315–323PubMed

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 26:10129–10140PubMed

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 43:321–332PubMed

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 168:184–194PubMed

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 39:409–421PubMed

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 19:255–257PubMed

142.

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

143.

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

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 18:417–421PubMed

145.

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

146.

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

147.

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

148.

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

149.

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

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 101:284–289PubMed

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 316:750–754PubMed

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 57:419–425PubMed

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 38:24–26PubMed

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 22:1679–1689PubMed

155.

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

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 282:35722–35732PubMed

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 215:173–176PubMed

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 14:457–466PubMed

159.

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

160.

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

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 25:6755–6764PubMed

163.

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

164.

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

165.

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

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 90:9649–9653PubMed

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 164:1495–1502PubMed

168.

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

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 20:1254–1256PubMed

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 14:837–842PubMed

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 22:9794–9799PubMed

172.

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

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 20:8717–8726PubMed

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 141:1031–1039PubMed

175.

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

176.

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

177.

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

178.

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

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 63:178–188PubMed

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 65:906–912PubMed

181.

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

182.

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

183.

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

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 56:933–944PubMed

185.

Tabira T, Chui DH, Kuroda S (2002) Significance of intracellular Abeta42 accumulation in Alzheimer’s disease. Front Biosci 7:a44–a49PubMed

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 24:3592–3599PubMed

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 161:1869–1879PubMed

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 282:18895–18906PubMed

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 29:9704–9713PubMed

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 2:93–95PubMed

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 30:572–580PubMed

193.

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

194.

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

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 271:8966–8970PubMed

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 29:241–252PubMed

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 286:735–741PubMed

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 416:535–539PubMed

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 29:10788–10801PubMed

200.

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

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 90:9513–9517PubMed

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 272:16085–16088PubMed

203.

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

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 91:513–520PubMed

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 306:116–120PubMed

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 117:85–96PubMed

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

208.

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

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 59:723–732PubMed

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 270:14786–14792PubMed

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 274:20650–20656PubMed

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 29:15660–15668PubMed

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 156:519–529PubMed

214.

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

Titel: Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease
verfasst von: Gunnar K. Gouras
Davide Tampellini
Reisuke H. Takahashi
Estibaliz Capetillo-Zarate
Publikationsdatum: 01.05.2010
Verlag: Springer-Verlag
Erschienen in: Acta Neuropathologica / Ausgabe 5/2010
Print ISSN: 0001-6322
Elektronische ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-010-0679-9

Leitlinien kompakt für die Neurologie

Mit medbee Pocketcards sicher entscheiden.

^{Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag}

Kostenlos registrieren

Neu im Fachgebiet Neurologie

Akuter Schwindel: Wann lohnt sich eine MRT?

28.04.2024 Schwindel Nachrichten

Akuter Schwindel stellt oft eine diagnostische Herausforderung dar. Wie nützlich dabei eine MRT ist, hat eine Studie aus Finnland untersucht. Immerhin einer von sechs Patienten wurde mit akutem ischämischem Schlaganfall diagnostiziert.

Niedriger diastolischer Blutdruck erhöht Risiko für schwere kardiovaskuläre Komplikationen

25.04.2024 Hypotonie Nachrichten

Wenn unter einer medikamentösen Hochdrucktherapie der diastolische Blutdruck in den Keller geht, steigt das Risiko für schwere kardiovaskuläre Ereignisse: Darauf deutet eine Sekundäranalyse der SPRINT-Studie hin.

Frühe Alzheimertherapie lohnt sich

25.04.2024 AAN-Jahrestagung 2024 Nachrichten

Ist die Tau-Last noch gering, scheint der Vorteil von Lecanemab besonders groß zu sein. Und beginnen Erkrankte verzögert mit der Behandlung, erreichen sie nicht mehr die kognitive Leistung wie bei einem früheren Start. Darauf deuten neue Analysen der Phase-3-Studie Clarity AD.

Viel Bewegung in der Parkinsonforschung

25.04.2024 Parkinson-Krankheit Nachrichten

Neue arznei- und zellbasierte Ansätze, Frühdiagnose mit Bewegungssensoren, Rückenmarkstimulation gegen Gehblockaden – in der Parkinsonforschung tut sich einiges. Auf dem Deutschen Parkinsonkongress ging es auch viel um technische Innovationen.

Update Neurologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Springer Medizin

Abstract

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 5/2010

Gene expression analysis of the microvascular compartment in multiple sclerosis using laser microdissected blood vessels

Analysis of microdissected human neurons by a sensitive ELISA reveals a correlation between elevated intracellular concentrations of Aβ42 and Alzheimer’s disease neuropathology

Tumour cell migration in adamantinomatous craniopharyngiomas is promoted by activated Wnt-signalling

Accumulation of intraneuronal Aβ correlates with ApoE4 genotype

Kurt Jellinger Prize 2010 for Outstanding Scientific Writing in Neuropathology