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Article type: Research Article
Authors: Banwait, Suritaa | Galvan, Veronicaa | Zhang, Junlia | Gorostiza, Olivia F.a | Ataie, Marinaa | Huang, Weia | Crippen, Daniellea | Koo, Edward H.b | Bredesen, Dale E.a; c; *
Affiliations: [a] Buck Institute for Age Research, 8001 Redwood Blvd., Novato, CA 94945, USA | [b] University of California, San Diego, Department of Neuroscience, La Jolla, CA 92093, USA | [c] University of California, San Francisco, Department of Neurology, San Francisco, CA, 94143, USA
Correspondence: [*] Corresponding author. The Buck Institute for Age Research, 8001 Redwood Blvd., Novato, CA 94945, USA. Tel.: +1 415 209 2090; Fax: +1 415 209 2230; E-mail: dbredesen@buckinstitute.org.
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.
Keywords: Alzheimer's disease, Amyloid-β protein precursor, APP-C31, APPNeo, Asp664, proteolytic processing
DOI: 10.3233/JAD-2008-13101
Journal: Journal of Alzheimer's Disease, vol. 13, no. 1, pp. 1-16, 2008
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