C-terminal cleavage of the amyloid-β protein precursor at Asp664: A switch associated with Alzheimer's disease

Surita Banwait, Veronica Galvan, Junli Zhang, Olivia F. Gorostiza, Marina Ataie, Wei Huang, Danielle Crippen, Edward H. Koo, Dale E. Bredesen

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

In addition to the proteolytic cleavages that give rise to amyloid-β (Aβ), the amyloid-β protein precursor (AβPP) is cleaved at Asp664 intracytoplasmically. This cleavage releases a cytotoxic peptide, APP-C31, removes AβPP-interaction motifs required for signaling and internalization, and is required for the generation of AD-like deficits in a mouse model of the disease. Although we and others had previously shown that Asp664 cleavage of AβPP is increased in AD brains, the distribution of the Asp664-cleaved forms of AβPP in non-diseased and AD brains at different ages had not been determined. Confirming previous reports, we found that Asp664-cleaved forms of AβPP were increased in neuronal cytoplasm and nuclei in early-stage AD brains but were absent in age-matched, non-diseased control brains and in late-stage AD brains. Remarkably, however, Asp664-cleaved AβPP was prominent in neuronal somata and in processes in entorhinal cortex and hippocampus of non-diseased human brains at ages <45 years. Our observations suggest that Asp664 cleavage of AβPP may be part of the normal proteolytic processing of AβPP in young (<45 years) human brain and that this cleavage is down-regulated with normal aging, but is aberrantly increased and altered in location in early AD.

Original languageEnglish (US)
Pages (from-to)1-16
Number of pages16
JournalJournal of Alzheimer's Disease
Volume13
Issue number1
DOIs
StatePublished - 2008

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Keywords

  • APP-C31
  • APPNeo
  • Alzheimer's disease
  • Amyloid-β protein precursor
  • Asp664
  • Proteolytic processing

ASJC Scopus subject areas

  • Neuroscience(all)
  • Clinical Psychology
  • Geriatrics and Gerontology
  • Psychiatry and Mental health

Cite this

Banwait, S., Galvan, V., Zhang, J., Gorostiza, O. F., Ataie, M., Huang, W., Crippen, D., Koo, E. H., & Bredesen, D. E. (2008). C-terminal cleavage of the amyloid-β protein precursor at Asp664: A switch associated with Alzheimer's disease. Journal of Alzheimer's Disease, 13(1), 1-16. https://doi.org/10.3233/JAD-2008-13101