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γ-Secretase Modulators as Aβ42-Lowering Pharmacological Agents to Treat Alzheimer’s Disease

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Alzheimer’s Disease II

Part of the book series: Topics in Medicinal Chemistry ((TMC,volume 24))

Abstract

γ-Secretase is an intramembrane aspartyl protease comprised of four essential subunits including presenilin, nicastrin (NCT), anterior pharynx defective 1 (Aph-1), and presenilin enhancer 2 (Pen-2). The amyloid precursor protein (APP) is cleaved sequentially by β-secretase and γ-secretase to generate Aβ peptides including neurotoxic Aβ42 monomers and oligomers that are believed to be key pathological species in AD. Familial Alzheimer’s disease (FAD) mutations in presenilin and APP increase the relative proportion of Aβ42. γ-Secretase modulators (GSMs) have been discovered that bind to presenilin and selectively modulate γ-secretase proteolytic activity. Importantly, GSMs have the opposite effect on the Aβ cleavage profile as compared to FAD mutations, namely they decrease the relative proportion of Aβ42. This review will discuss the initial discovery of GSMs and the recent progress leading to the development of GSMs with improved drug-likeness. These efforts have culminated in GSMs that are currently undergoing proof-of-mechanism studies in the clinic, which is a significant step forward toward testing the amyloid hypothesis.

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    Douglas S. Johnson & Martin Pettersson

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    Michael S. Wolfe

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Johnson, D.S., Pettersson, M. (2017). γ-Secretase Modulators as Aβ42-Lowering Pharmacological Agents to Treat Alzheimer’s Disease. In: Wolfe, M. (eds) Alzheimer’s Disease II. Topics in Medicinal Chemistry, vol 24. Springer, Cham. https://doi.org/10.1007/7355_2016_19

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