Alzheimer's disease (AD) is a progressive neurodegenerative disorder pathologically characterized by deposition of ␤-amyloid (A␤) peptides as senile plaques in the brain. Recent studies suggest that green tea flavonoids may be used for the prevention and treatment of a variety of neurodegenerative diseases. Here, we report that (-)-epigallocatechin-3-gallate (EGCG), the main polyphenolic constituent of green tea, reduces A␤ generation in both murine neuron-like cells (N2a) transfected with the human "Swedish" mutant amyloid precursor protein (APP) and in primary neurons derived from Swedish mutant APP-overexpressing mice (Tg APP sw line 2576). In concert with these observations, we find that EGCG markedly promotes cleavage of the ␣-C-terminal fragment of APP and elevates the N-terminal APP cleavage product, soluble APP-␣. These cleavage events are associated with elevated ␣-secretase activity and enhanced hydrolysis of tumor necrosis factor ␣-converting enzyme, a primary candidate ␣-secretase. As a validation of these findings in vivo, we treated Tg APP sw transgenic mice overproducing A␤ with EGCG and found decreased A␤ levels and plaques associated with promotion of the nonamyloidogenic ␣-secretase proteolytic pathway. These data raise the possibility that EGCG dietary supplementation may provide effective prophylaxis for AD.

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Forkhead box class O (FOXO) proteins are transcription factors that function downstream of the PTEN tumor suppressor and directly control the expression of genes involved in apoptosis, cell cycle progression, and stress responses. In the present study, we show that FOXO1 interacts with four and a half LIM 2 (FHL2) in prostate cancer cells. This interaction occurred in the nucleus and was enhanced by lysophosphatic acid. FHL2 decreased the transcriptional activity of FOXO1 and the expression of known FOXO target genes and inhibited FOXO1-induced apoptosis. Interestingly, SIRT1, a mammalian homolog of yeast Sir2, bound to and deacetylated FOXO1 and inhibited its transcriptional activity. FHL2 enhanced the interaction of FOXO1 and SIRT1 and the deacetylation of FOXO1 by Sirtuin-1 (SIRT1). Overall, our data show that FHL2 inhibits FOXO1 activity in prostate cancer cells by promoting the deacetylation of FOXO1 by SIRT1.