Proteolytic processing of the Alzheimer's disease amyloid precursor protein in brain and platelets

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Abstract
Proteolytic processing of the amyloid precursor protein by β ‐and γ‐secretases results in the production of Alzheimer's disease (AD) Aβ amyloid peptides. Modulation of secretase activity is being investigated as a potential therapeutic approach. Recent studies with human brain have revealed that the β‐secretase protein, BACE, is increased in cortex of AD patients. Analysis of βCTF (or C99), the amyloid precursor protein (APP) product of BACE cleavage that is the direct precursor to Aβ, shows it is also elevated in AD, underlying the importance of β‐secretase cleavage in AD pathogenesis. The C‐terminal product of γ‐secretase cleavage of APP, ϵCTF (or AICD), is enriched in human brain cortical nuclear fractions, a subcellular distribution appropriate for a putative involvement of APP cytosolic domain in signal transduction. Analysis of AD cortex samples, particularly that of a carrier of a familial APP mutation, suggests that processing of APP transmembrane domain generates an alternative CTF product. All these particularities observed in the AD brain demonstrate that APP processing is altered in AD. The transgenic mouse model Tg2576 seems to be a promising laboratory tool to test potential modulators of Aβ formation. Indeed, C‐terminal products of α‐, β‐, and γ‐secretase cleavage are readily detectable in the brain of these transgenic mice. Finally, the finding of the same secretase products in platelets and neurons make platelets a potentially useful and easily accessible clinical tool to monitor effects of novel therapies based on inhibition of β‐ or γ‐secretase.