Role of the APP non-amyloidogenic signaling pathway and targeting α-secretase as an alternative drug target for treatment of Alzheimer's diseases

S. Bandyopadhyay, L. E. Goldstein, D. K. Lahiri, J. T. Rogers

Research output: Contribution to journalReview article

57 Scopus citations

Abstract

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), allowed by counter-screens 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.

Original languageEnglish (US)
Pages (from-to)2848-2864
Number of pages17
JournalCurrent Medicinal Chemistry
Volume14
Issue number27
DOIs
StatePublished - Nov 1 2007

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Keywords

  • ADAM activators
  • APP proteolysis
  • Drug screens
  • Interleukin-1
  • Signaling
  • Soluble sAPPα

ASJC Scopus subject areas

  • Organic Chemistry
  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry
  • Pharmacology

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