C-terminal cleavage of the amyloid-beta protein precursor at Asp664: a switch associated with Alzheimer's disease.
In addition to the proteolytic cleavages that give rise to amyloid-beta (Abeta), the amyloid-beta protein precursor (AbetaPP) is cleaved at Asp664 intracytoplasmically. This cleavage releases a cytotoxic peptide, APP-C31, removes AbetaPP-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 AbetaPP is increased in AD brains, the distribution of the Asp664-cleaved forms of AbetaPP in non-diseased and AD brains at different ages had not been determined. Confirming previous reports, we found that Asp664-cleaved forms of AbetaPP 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 AbetaPP 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 AbetaPP may be part of the normal proteolytic processing of AbetaPP 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.
Banwait
Surita
S
Buck Institute for Age Research, 8001 Redwood Boulevard, Novato, CA 94945, USA.
Galvan
Veronica
V
Zhang
Junli
J
Gorostiza
Olivia F
OF
Ataie
Marina
M
Huang
Wei
W
Crippen
Danielle
D
Koo
Edward H
EH
Bredesen
Dale E
DE
D000368:Aged; D000369:Aged, 80 and over; D000429:Alcohol Oxidoreductases / Q000235:genetics* / Q000378:metabolism; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics* / Q000378:metabolism; D001224:Aspartic Acid / Q000235:genetics* / Q000378:metabolism; D039241:Cleavage Stimulation Factor / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005812:Genes, Switch / Q000235:genetics*; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D008297:Male; D015398:Signal Transduction / Q000502:physiology
D016564:Amyloid beta-Protein Precursor; D039241:Cleavage Stimulation Factor; D004268:DNA-Binding Proteins; D001224:Aspartic Acid; D000429:Alcohol Oxidoreductases; C096794:C-terminal binding protein