Recently, we have shown that green tea polyphenol (–)-epigallocatechin-3-gallate (EGCG) exerts a beneficial role on reducing brain Aβ levels, resulting in mitigation of cerebral amyloidosis in a mouse model of Alzheimer disease. EGCG seems to accomplish this by modulating amyloid precursor protein (APP) processing, resulting in enhanced cleavage of the α-COOH-terminal fragment (α-CTF) of APP and corresponding elevation of the NH2-terminal APP product, soluble APP-α (sAPP-α). These beneficial effects were associated with increased α-secretase cleavage activity, but no significant alteration in β-or γ-secretase activities. To gain insight into the molecular mechanism whereby EGCG modulates APP processing, we evaluated the involvement of three candidateα-secretase enzymes, a-disintegrin and metalloprotease (ADAM) 9, 10, or 17, in EGCG-induced non-amyloidogenic APP metabolism. Results show that EGCG treatment of N2a cells stably transfected with “Swedish” mutant human APP (SweAPP N2a cells) leads to markedly elevated active (∼60 kDa mature form) ADAM10 protein. Elevation of active ADAM10 correlates with increased α-CTF cleavage, and elevated sAPP-α. To specifically test the contribution of ADAM10 to non-amyloidogenic APP metabolism, small interfering RNA knockdown of ADAM9, -10, or -17 mRNA was employed. Results show that ADAM10 (but not ADAM9 or -17) is critical for EGCG-mediated α-secretase cleavage activity. In summary, ADAM10 activation is necessary for EGCG promotion of non-amyloidogenic (α-secretase cleavage) APP processing. Thus, ADAM10 represents an important pharmacotherapeutic target for the treatment of cerebral amyloidosis in Alzheimer disease.
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