New precision medicine avenues to the prevention of Alzheimer's disease from insights into the structure and function of γ-secretases.

ABSTRACT: Two phase-III clinical trials with anti-amyloid peptide antibodies have met their primary goal, i.e. slowing of Alzheimer's disease (AD) progression. However, antibody therapy may not be the optimal therapeutic modality for AD prevention, as we will discuss in the context of the earlier small molecules described as "γ-secretase modulators" (GSM). We review here the structure, function, and pathobiology of γ-secretases, with a focus on how mutations in presenilin genes result in early-onset AD. Significant progress has been made in generating compounds that act in a manner opposite to pathogenic presenilin mutations: they stabilize the proteinase-substrate complex, thereby increasing the processivity of substrate cleavage and altering the size spectrum of Aβ peptides produced. We propose th

SUBMITTER: De Strooper B 

PROVIDER: S-EPMC10943082 | biostudies-literature | 2024 Mar

REPOSITORIES: biostudies-literature