New precision medicine avenues to the prevention of Alzheimer's disease from insights into the structure and function of γ-secretases.
Alzheimer
Cancer
Gamma-secretase-modulator
Presenilin
γ-Secretase Allosteric Stabilizer
Journal
The EMBO journal
ISSN: 1460-2075
Titre abrégé: EMBO J
Pays: England
ID NLM: 8208664
Informations de publication
Date de publication:
Mar 2024
Mar 2024
Historique:
received:
18
11
2023
accepted:
06
02
2024
revised:
20
01
2024
medline:
18
3
2024
pubmed:
24
2
2024
entrez:
24
2
2024
Statut:
ppublish
Résumé
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 the term "γ-secretase allosteric stabilizers" (GSAS) to distinguish these compounds from the rather heterogenous class of GSM. The GSAS represent, in theory, a precision medicine approach to the prevention of amyloid deposition, as they specifically target a discrete aspect in a complex cell biological signalling mechanism that initiates the pathological processes leading to Alzheimer's disease.
Identifiants
pubmed: 38396302
doi: 10.1038/s44318-024-00057-w
pii: 10.1038/s44318-024-00057-w
pmc: PMC10943082
doi:
Substances chimiques
Amyloid Precursor Protein Secretases
EC 3.4.-
Amyloid beta-Peptides
0
Presenilins
0
Presenilin-1
0
Amyloid beta-Protein Precursor
0
Types de publication
Journal Article
Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
887-903Subventions
Organisme : EC | European Research Council (ERC)
ID : ERC-834682
Organisme : UK Research and Innovation (UKRI)
ID : MR/Y014847/1
Informations de copyright
© 2024. The Author(s).
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