Distinct spatiotemporal accumulation of N-truncated and full-length amyloid-β42 in Alzheimer's disease

Mitsuru Shinohara, Shunsuke Koga, Takuya Konno, Jeremy Nix, Motoko Shinohara, Naoya Aoki, Pritam Das, Joseph E Parisi, Ronald Carl Petersen, Terrone L. Rosenberry, Dennis W Dickson, Guojun D Bu

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

Accumulation of amyloid-β peptides is a dominant feature in the pathogenesis of Alzheimer's disease; however, it is not clear how individual amyloid-β species accumulate and affect other neuropathological and clinical features in the disease. Thus, we compared the accumulation of N-terminally truncated amyloid-β and full-length amyloid-β, depending on disease stage as well as brain area, and determined how these amyloid-β species respectively correlate with clinicopathological features of Alzheimer's disease. To this end, the amounts of amyloid-β species and other proteins related to amyloid-β metabolism or Alzheimer's disease were quantified by enzymelinked immunosorbent assays (ELISA) or theoretically calculated in 12 brain regions, including neocortical, limbic and subcortical areas from Alzheimer's disease cases (n = 19), neurologically normal elderly without amyloid-β accumulation (normal ageing, n = 13), and neurologically normal elderly with cortical amyloid-β accumulation (pathological ageing, n = 15). We observed that N-terminally truncated amyloid-β42 and full-length amyloid-β42 accumulations distributed differently across disease stages and brain areas, while Nterminally truncated amyloid-β40 and full-length amyloid-β40 accumulation showed an almost identical distribution pattern. Cortical N-terminally truncated amyloid-β42 accumulation was increased in Alzheimer's disease compared to pathological ageing, whereas cortical full-length amyloid-β42 accumulation was comparable between Alzheimer's disease and pathological ageing. Moreover, Nterminally truncated amyloid-β42 were more likely to accumulate more in specific brain areas, especially some limbic areas, while fulllength amyloid-β42 tended to accumulate more in several neocortical areas, including frontal cortices. Immunoprecipitation followed by mass spectrometry analysis showed that several N-terminally truncated amyloid-β42 species, represented by pyroglutamylated amyloid-β11-42, were enriched in these areas, consistent with ELISA results. N-terminally truncated amyloid-β42 accumulation showed significant regional association with BACE1 and neprilysin, but not PSD95 that regionally associated with full-length amyloid-b42 accumulation. Interestingly, accumulations of tau and to a greater extent apolipoprotein E (apoE, encoded by APOE) were more strongly correlated with N-terminally truncated amyloid-β42 accumulation than those of other amyloid-β species across brain areas and disease stages. Consistently, immunohistochemical staining and in vitro binding assays showed that apoE co-localized and bound more strongly with pyroglutamylated amyloid-β11-x fibrils than full-length amyloid-β fibrils. Retrospective review of clinical records showed that accumulation of N-terminally truncated amyloid-β42 in cortical areas was associated with disease onset, duration and cognitive scores. Collectively, N-terminally truncated amyloid-β42 species have spatiotemporal accumulation patterns distinct from full-length amyloid-β42, likely due to different mechanisms governing their accumulations in the brain. These truncated amyloid-β species could play critical roles in the disease by linking other clinicopathological features of Alzheimer's disease.

Original languageEnglish (US)
Pages (from-to)3301-3316
Number of pages16
JournalBrain
Volume140
Issue number12
DOIs
StatePublished - Dec 1 2017

Keywords

  • Alzheimer's disease
  • amyloid-β
  • apoE
  • neuropathology
  • tau

ASJC Scopus subject areas

  • Clinical Neurology

Fingerprint Dive into the research topics of 'Distinct spatiotemporal accumulation of N-truncated and full-length amyloid-β<sub>42</sub> in Alzheimer's disease'. Together they form a unique fingerprint.

  • Cite this

    Shinohara, M., Koga, S., Konno, T., Nix, J., Shinohara, M., Aoki, N., Das, P., Parisi, J. E., Petersen, R. C., Rosenberry, T. L., Dickson, D. W., & Bu, G. D. (2017). Distinct spatiotemporal accumulation of N-truncated and full-length amyloid-β42 in Alzheimer's disease. Brain, 140(12), 3301-3316. https://doi.org/10.1093/brain/awx284