Amyloid precursor protein (APP) proteolysis is required for production of amyloid-b (Ab) peptides that comprise b-amyloid\r\nplaques in brains of Alzheimer�s disease (AD) patients. Recent AD therapeutic interest has been directed toward a group of\r\nanti-amyloidogenic compounds extracted from plants. We orally administered the brain penetrant, small molecule phenolic\r\ncompound ferulic acid (FA) to the transgenic PSAPP mouse model of cerebral amyloidosis (bearing mutant human APP and\r\npresenilin-1 transgenes) and evaluated behavioral impairment and AD-like pathology. Oral FA treatment for 6 months\r\nreversed transgene-associated behavioral deficits including defective: hyperactivity, object recognition, and spatial working\r\nand reference memory, but did not alter wild-type mouse behavior. Furthermore, brain parenchymal and cerebral vascular\r\nb-amyloid deposits as well as abundance of various Ab species including oligomers were decreased in FA-treated PSAPP\r\nmice. These effects occurred with decreased cleavage of the b-carboxyl-terminal APP fragment, reduced b-site APP cleaving\r\nenzyme 1 protein stability and activity, attenuated neuroinflammation, and stabilized oxidative stress. As in vitro validation,\r\nwe treated well-characterized mutant human APP-overexpressing murine neuron-like cells with FA and found significantly\r\ndecreased Ab production and reduced amyloidogenic APP proteolysis. Collectively, these results highlight that FA is a bsecretase\r\nmodulator with therapeutic potential against AD.
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