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 language | English (US) |
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Pages (from-to) | 1-16 |
Number of pages | 16 |
Journal | Journal of Alzheimer's Disease |
Volume | 13 |
Issue number | 1 |
DOIs | |
State | Published - 2008 |
Externally published | Yes |
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