The pathological hallmark of Alzheimer's Disease (AD) is the presence of insoluble plaques in the extracellular space of the brain. These plaques are composed primarily of A� peptide, which results from the sequential cleavage of amyloid precursor protein by �- and ?-secretase. The plaques also contain high amounts of metals, particularly copper and zinc. Copper bound to A� is known to catalyze various types of oxidative stress reactions, the products of which are found extensively in the AD brain. Here we present a prochelator (SWH) that is converted to a copper chelator (CP) when ezymatically hydrolyzed by �-secretase (BACE).  This approach imparts spatial control by unveiling the chelator at the site of A� production. Membrane targeting with a dihydrocholesterol moiety not only allows for SWH to be hydrolyzed in living cells, but enhances the efficacy of the chelator by targeting it to a site of A�-Cu toxicity.

BACE activated prochelator mediates Aβ-Cu toxicity in an Alzheimer's disease cell model

243rd National Meeting (2012)

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