Background: Upregulation of Cancerous Inhibitor of PP2A (CIP2A) plays an important role
in disease-related phosphorylation of tau/APP and tau pathology/Aβ overproduction through inhibiting
PP2A in AD brain. Genistein has been shown to potently reduce CIP2A in experimental cancer treatment
research. Whether Genistein can ameliorate AD pathology through targeting CIP2A needs further investigation.
Methods: The inhibitory effects of Genistein on tau/APP phosphorylation and Aβ overproduction in AD
cell models have been explored. HEK293-T cells were co-transfected with CIP2A and APP plasmids, or
CIP2A and tau plasmids, with Genistein incubation at 0, 30, 60 or 120 µM for 48 h, cell viability and
PP2A activities were measured. HEK293-T cells with CIP2A/APP overexpression treated with Genistein
at 30 µM for 48 h were collected and lyzed for Western blotting detection of CIP2A, PP2Ac, APP-T668,
total APP, PS1, BACE1, sAPPα and sAPPβ. Aβ40 and Aβ42 levels in cell supernatant, soluble fraction
(RIPA) and insoluble fraction (formic acid soluble) of cell lysates were measured by ELISA. HEK293-T
cells with CIP2A/tau overexpression treated with Genistein at 30 µM for 48 h were collected for Western
blotting detection of CIP2A, PP2Ac, tau-S396, tau-S404 and total tau.
Results: Genistein effectively reduced CIP2A expression, and restored PP2A activities both in
CIP2A/APP, CIP2A/tau co-expressed cells. Genistein reduced APP phosphorylation at T668 site and
inhibited Aβ production. Meantime, Genistein ameliorated tau hyperphosphorylation through repressing
the inhibitory effect of CIP2A on PP2A.
Conclusion: CIP2A is a target of Genistein in AD therapy. Genistein reduces APP/tau hyperphosphorylation
and Aβ production through inhibiting the effect of CIP2A on PP2A.