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

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

Research output: Contribution to journalArticle

29 Citations (Scopus)

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
StatePublished - 2008
Externally publishedYes

Fingerprint

Amyloid beta-Protein Precursor
Alzheimer Disease
Brain
Protein Interaction Domains and Motifs
Entorhinal Cortex
Carisoprodol
Amyloid
Hippocampus
Cytoplasm
Peptides

Keywords

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

ASJC Scopus subject areas

  • Neuropsychology and Physiological Psychology

Cite this

Banwait, S., Galvan Hart, V., Zhang, J., Gorostiza, O. F., Ataie, M., Huang, W., ... 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.

C-terminal cleavage of the amyloid-β protein precursor at Asp664 : A switch associated with Alzheimer's disease. / Banwait, Surita; Galvan Hart, Veronica; Zhang, Junli; Gorostiza, Olivia F.; Ataie, Marina; Huang, Wei; Crippen, Danielle; Koo, Edward H.; Bredesen, Dale E.

In: Journal of Alzheimer's Disease, Vol. 13, No. 1, 2008, p. 1-16.

Research output: Contribution to journalArticle

Banwait, S, Galvan Hart, V, Zhang, J, Gorostiza, OF, Ataie, M, Huang, W, Crippen, D, Koo, EH & Bredesen, DE 2008, 'C-terminal cleavage of the amyloid-β protein precursor at Asp664: A switch associated with Alzheimer's disease', Journal of Alzheimer's Disease, vol. 13, no. 1, pp. 1-16.
Banwait, Surita ; Galvan Hart, Veronica ; Zhang, Junli ; Gorostiza, Olivia F. ; Ataie, Marina ; Huang, Wei ; Crippen, Danielle ; Koo, Edward H. ; Bredesen, Dale E. / C-terminal cleavage of the amyloid-β protein precursor at Asp664 : A switch associated with Alzheimer's disease. In: Journal of Alzheimer's Disease. 2008 ; Vol. 13, No. 1. pp. 1-16.
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