P 077 - Clearing Amyloid-β through PPARγ/ApoE Activation by Genistein is a Treatment of Experimental Alzheimer's Disease

Abstract

Amyloid-b (Ab) clearance from brain, which is decreased in Alzheimer's disease, is facilitated by apolipoprotein E (ApoE). ApoE is upregulated by activation of the retinoid X receptor moiety of the RXR/PPAR dimeric receptor. As we have previously demonstrated, estrogenic compounds, such as genistein, have antioxidant activity, which can be evidenced by increased expression of manganese superoxide dismutase (MnSOD). Furthermore, genistein is a non-toxic, well-tested, and inexpensive drug that activates PPARg receptor. We isolated and cultured cortical astrocytes from dissected cerebral cortices of neonatal mice (C57BL/6 J). Preincubation with genistein (5 mM) for 24 hours, prior to the addition of Ab (5 mM) increased ApoE release to the culture medium in a concentration dependent manner. This effect is mediated by activation of PPARg as its inhibition significantly prevents the increase in genistein- induced ApoE release. Finally, treatment of an Alzheimer's disease mouse model with genistein was associated with a lowering of Ab levels in brain, in the number and the area of amyloid plaques (confirmed in vivo by positron emission tomography) as well as in microglial reactivity. Our results strongly suggest that controlled clinical trials should be performed to test the effect of genistein as treatment of human Alzheimer's disease.