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.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-016-0294-7) contains supplementary material, which is available to authorized users.

Chemical imaging of evolving amyloid plaque pathology and associated Aβ peptide aggregation in a transgenic mouse model of Alzheimer’s disease

“…The tgAPP SWE mouse model appeared to exhibit primarily C-terminally truncated peptides. Here, as previously shown through IHC, Ab1-40, Ab1-39, Ab1-38, and Ab1-37 were observed along with the commonly recognized Ab1-42 (Reinert et al 2016). In agreement with previous observations in tgAPP ArcSwe mice, Ab1-40 was found in our study to be the primary Ab peptide species in the observed Ab plaques (Carlred et al 2016).…”

“…In line with these data, plaque pathology-associated deposition of multiple C-terminally truncated peptides (Ab1-37, Ab1-38, Ab1-39 and Ab1-40) was previously described for familial AD (FAD) cases with the Swedish APP mutation (Reinert et al 2014;Reinert et al 2016) as well as in various transgenic mouse models carrying this mutation (Hsiao et al 1996;Kawarabayashi et al 2001;Kuo et al 2001;Reinert et al 2016).…”

The metalloprotease ADAMTS4 generates N-truncated Aβ4–x species and marks oligodendrocytes as a source of amyloidogenic peptides in Alzheimer’s disease

“…To validate the relevance of ADAMTS4 for Aβ generation and APP processing in vivo, ADAMTS4 −/− knockout (KO) mice were crossed to the 5xFAD model of AD [54,61]. Consistent with previous results [62], mass spectrometry analysis of Aβ peptide species in the brains of 12-month-old Supplementary Fig. S4).…”

Generation of Amyloid‐β Peptides by γ‐Secretase

“…From these, M139V (TM2), M146L (TM2), L166P (TM2), and G384A (TM7) mutations have been associated with an increase in Aβ42 production, due to conformational alterations in PS1 and PS1‐APP complex interactions ,. These changes in the PS1 conformation have also been observed in the TM6–TM7 loop with both exon 9 deletion (E9Δ, T291_S319del) and L286V mutation ,. Moreover, a previous study demonstrated that the PS1 protein with E9Δ is not subject to endoproteolytic processing, since this lacks the cleavage site .…”