Secretase inhibitors and modulators for Alzheimer’s disease treatment

Abstract

Genetic and biological studies provide strong evidence that the deposition of amyloid-β peptide (Aβ) contributes to the etiology of Alzheimer’s disease (AD). Aβ is generated from amyloid-β precursor protein by β- and γ-secretases, which are plausible molecular targets for AD treatment. Thus, drugs that regulate the production of Aβ by inhibiting or modulating secretase activity could provide effective therapeutics for AD. Both secretases are transmembrane proteases: β-site amyloid-β precursor protein cleaving enzyme 1, the main neuronal β-secretase, is a single span transmembrane aspartyl protease; γ-secretase is a multiprotein complex comprising four core subunits that are all transmembrane proteins: presenilin, nicastrin, anterior pharynx-defective 1 and presenilin enhancer 2. Molecular biochemical, enzymological and genetic analyses reveal the molecular mechanisms of these secretases in the generation of Aβ. Moreover, extensive drug screening and development have enabled some secretase inhibitors and modulators to advance into late-Phase clinical trials. This review focuses on recent progresses in β- and γ-secretase biology, including the proteolytic mechanism, regulation and composition of these enzymes. Moreover, this review discusses the recent development of inhibitors, and provides a direction for the effective treatment of AD through inhibition/modulation of β- and γ-secretase activities.

Keywords::

• Alzheimer’s disease
• amyloid-β protein
• amyloid precursor protein
• Notch
• secretase
• lipid raft
• inhibitor
• modulator
• vesicle trafficking

Acknowledgements

I would like to thank Takeshi Iwatsubo (The University of Tokyo) and several collaborators for supporting my research over a long period of time. I also acknowledge the previous and current members of our department for helpful discussions and technical assistance.

Financial & competing interests disclosure

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.