Event Information
Beta-Secretase Activated Prochelator
- Abstract:
According to the Amyloid Cascade Hypothesis, Alzheimer’s disease is characterized by the formation of plaques composed of amyloid-â peptide (Aâ) fragments. The aggregation of Aâ into fibrils, and ultimately plaques, is greatly exacerbated in the presence of copper and zinc. Additionally, the Aâ-Cu complex has been implicated in the production of reactive oxygen species that have a range of neurotoxic effects commonly associated with Alzheimer’s. The present work describes the peptide prochelator SWH (EVNLDAHFWADR) that is activated upon proteolysis by â-secretase to the copper chelator CP (DAHFWADR). CP shows the ability to sequester copper (log K’ = 12.6 at pH 7.4) from Aâ, protect against reactive oxygen species formation, and reverse Cu-induced Aâ aggregation. Furthermore, enzymatic activation at the site of Aâ production could allow CP to directly target the copper in Aâ plaques, addressing a common shortcoming with more general chelators. Such a design strategy could eventually lead to novel Alzheimer’s treatments which target the pathology of the disease.
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