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Role of the APP Non-Amyloidogenic Signaling Pathway and Targeting α-Secretase as an Alternative Drug Target for Treatment of Alzheimer's Disease

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Alzheimer's disease (AD) is the most prevalent form of dementia, and its effective disease modifying therapies are desperately needed. Promotion of non-amyloidogenic alpha (α)-secretase cleavage of amyloid precursor protein (APP) to release soluble sAPPα, based on the most widely accepted “amyloid model” as a plausible mechanism for AD treatment, is the focus of this review. Modulation of α-secretase or “a disintegrin and metalloprotease (ADAM)”s activity via protein kinase C (PKC), calcium ion (Ca2+), tyrosine kinase (TK), MAP kinase (MAPK), and hormonal signaling, which regulate catabolic processing of APP, are discussed. The inhibition of amyloidogenic processing of APP by the beta (β)-and gamma (γ)-secretase has been considered till now a promising strategy to treat AD. But β- and γ-secretase inhibitors, along with the available therapeutic tools for AD, have side effects. These challenges can be circumvented to certain extent; but activation of sAPPα release appears to be a potential alternative strategy to reduce cerebral amyloidosis. Drug screens have been performed to identify therapeutics for AD, but an effective screening strategy to isolate activators of α-secretase has been rarely reported. Novel reporter-based screens targeted toward APP mRNA 5' untranslated region (UTR), followed by counterscreens to detect α-secretase stimulators, could be important in detecting compounds to promote sAPPα release and reduce amyloid beta (Aβ) buildup. The primary inflammatory cytokine interleukin-1, which stimulates APP 5'UTR-directed translation of cell-associated APP, enhances processing to sAPPα in astrocytes and co-activates ADAM-10/ADAM-17 through MAPK signaling; thus illustrating a novel pathway that could serve as therapeutic model for AD.

Keywords: ADAM activators; APP proteolysis; drug screens; interleukin-1; signaling; soluble sAPPĪ±

Document Type: Research Article


Affiliations: Laboratory for Neurochemistry,Department of Psychiatry-Neuroscience, and Genetics and Aging Research Unit,Massachusetts General Hospital, Boston, Mass, USA.

Publication date: November 1, 2007

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  • Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews written by leaders in the field covering a range of the current topics in medicinal chemistry. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.

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