title: Deposition of C-terminally truncated Aβ species Aβ37 and Aβ39 in Alzheimer's disease and transgenic mouse models.
abstract: In Alzheimer's disease (AD) a variety of amyloid β-peptides (Aβ) are deposited in the form of extracellular diffuse and neuritic plaques (NP), as well as within the vasculature. The generation of Aβ from its precursor, the amyloid precursor protein (APP), is a highly complex procedure that involves subsequent proteolysis of APP by β- and γ-secretases. Brain accumulation of Aβ due to impaired Aβ degradation and/or altered ratios between the different Aβ species produced is believed to play a pivotal role in AD pathogenesis. While the presence of Aβ40 and Aβ42 in vascular and parenchymal amyloid have been subject of extensive studies, the deposition of carboxyterminal truncated Aβ peptides in AD has not received comparable attention. In the current study, we for the first time demonstrate the immunohistochemical localization of Aβ37 and Aβ39 in human sporadic AD (SAD). Our study further included the analysis of familial AD (FAD) cases carrying the APP mutations KM670/671NL, E693G and I716F, as well as a case of the PSEN1 ΔExon9 mutation. Aβ37 and Aβ39 were found to be widely distributed within the vasculature in the brains of the majority of studied SAD and FAD cases, the latter also presenting considerable amounts of Aβ37 containing NPs. In addition, both peptides were found to be present in extracellular plaques but only scarce within the vasculature in brains of a variety of transgenic AD mouse models. Taken together, our study indicates the importance of C-terminally truncated Aβ in sporadic and familial AD and raises questions about how these species are generated and regulated.
authors.affiliation: Division of Molecular Psychiatry, University Medical Center (UMG), Georg-August-University, Göttingen, Germany.
authors.forename: Jochim
authors.initials: J
authors.lastname: Reinert
authors.affiliation: Division of Molecular Psychiatry, University Medical Center (UMG), Georg-August-University, Göttingen, Germany.
authors.forename: Bernhard C
authors.initials: BC
authors.lastname: Richard
authors.affiliation: Department of Psychiatry and Psychotherapy, University Medical Center (UMG), Georg-August-University, von-Siebold-Str. 5, 37075, Göttingen, Germany.
authors.forename: Hans W
authors.initials: HW
authors.lastname: Klafki
authors.affiliation: Synaptic Systems, Göttingen, Germany.
authors.forename: Beate
authors.initials: B
authors.lastname: Friedrich
authors.affiliation: Division of Molecular Psychiatry, University Medical Center (UMG), Georg-August-University, Göttingen, Germany.|Department of Psychiatry and Psychotherapy, University Medical Center (UMG), Georg-August-University, von-Siebold-Str. 5, 37075, Göttingen, Germany.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Bayer
authors.affiliation: Department of Psychiatry and Psychotherapy, University Medical Center (UMG), Georg-August-University, von-Siebold-Str. 5, 37075, Göttingen, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Wiltfang
authors.affiliation: Institute of Neurology, Medical University of Vienna, Vienna, Austria.
authors.forename: Gabor G
authors.initials: GG
authors.lastname: Kovacs
authors.affiliation: Department of Public Health and Caring Sciences, Rudbeck Laboratory, University of Uppsala, Uppsala, Sweden.
authors.forename: Martin
authors.initials: M
authors.lastname: Ingelsson
authors.affiliation: Department of Public Health and Caring Sciences, Rudbeck Laboratory, University of Uppsala, Uppsala, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Lannfelt
authors.affiliation: Department of Pathology, University and University Hospital of Helsinki, Helsinki, Finland.
authors.forename: Anders
authors.initials: A
authors.lastname: Paetau
authors.affiliation: Analytical Chemistry, Department of Chemistry - Biomedical Centre and SciLifeLab, Uppsala University, Uppsala, Sweden.
authors.forename: Jonas
authors.initials: J
authors.lastname: Bergquist
authors.affiliation: Division of Molecular Psychiatry, University Medical Center (UMG), Georg-August-University, Göttingen, Germany. owirths@gwdg.de.|Department of Psychiatry and Psychotherapy, University Medical Center (UMG), Georg-August-University, von-Siebold-Str. 5, 37075, Göttingen, Germany. owirths@gwdg.de.
authors.forename: Oliver
authors.initials: O
authors.lastname: Wirths
mesh_terms: D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001921:Brain / Q000473:pathology*; D004195:Disease Models, Animal; D004314:Down Syndrome / Q000235:genetics / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010446:Peptide Fragments / Q000378:metabolism; D053764:Presenilin-1 / Q000235:genetics
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments; D053764:Presenilin-1