γ-Secretase and its modulators: Twenty years and beyond

Xia, Weiming

doi:10.1016/j.neulet.2019.02.011

Cited by 54Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchCholinesterase and Neurodegenerative Diseases

γ-Secretase and its modulators: Twenty years and beyond

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Xia, Weiming·2019·Neuroscience Letters

DOI 10.1016/j.neulet.2019.02.011PMC PMC7008970

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Abstract

Twenty years ago, Wolfe, Xia, and Selkoe identified two aspartate residues in Alzheimer's presenilin protein that constitute the active site of the γ-secretase complex. Mutations in the genes encoding amyloid precursor protein (APP) or presenilin (PS) cause early onset familial Alzheimer's disease (AD), and sequential cleavages of the APP by β-secretase and γ-secretase/presenilin generate amyloid β protein (Aβ), the major component of pathological hallmark, neuritic plaques, in brains of AD patients. Therapeutic strategies centered on targeting γ-secretase/presenilin to reduce amyloid were implemented and led to several high profile clinical trials. This review article focuses on the studies of γ-secretase and its inhibitors/modulators since the discovery of presenilin as the γ-secretase. While a lack of complete understanding of presenilin biology renders failure of clinical trials, the lessons learned from some γ-secretase modulators, while premature for human testing, provide new directions to develop potential therapeutics. Imbalanced Aβ homeostasis is an upstream event of neurodegenerative processes. Exploration of γ-secretase modulators for their roles in these processes is highly significant, e.g., decreasing neuroinflammation and levels of phosphorylated tau, the component of the other AD pathological hallmark, neurofibrillary tangles. Agents with excellent human pharmacology hold great promise in suppressing neurodegeneration in pre-symptomatic or early stage AD patients.

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Gamma-secretase modulators alter APP processing to lower Aβ42 and raise Aβ40 without affecting processing of other substrates.
“An alternative means of inhibiting amyloidogenic processing of Aβ by γ-secretase is to use γ-secretase modulators (GSM) that alter processing of APP (lower Aβ42 and higher Aβ40 levels) without influencing processing of other substrates (Xia, 2019).”
From Alzheimer Disease: An Update on Pathobiology and Treatment Strategies (2019) · cites this paper as Xia, 2019

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Shinpo (2000) · doi:10.1002/1097-4547(20001101)62:3

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Authors: Xia, W.
Affiliations: Boston University (US)
Corresponding author: Xia, Weiming
ORCID: Xia, Weiming
Venue: Neuroscience Letters
Publisher: Elsevier BV
Published: 2019-05
Volume: 701
Pages: 162-169
ISSN: 0304-3940 (ISSN-L)
DOI: 10.1016/j.neulet.2019.02.011
PMC: PMC7008970
OpenAlex: W2913752334
Cited by: 54
References: 135
Citations by year: 2026: 1 · 2025: 5 · 2024: 3 · 2023: 6 · 2022: 9 · 2021: 11 · 2020: 8 · 2019: 11
FWCI: 1.15
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
Locations: Neuroscience Letters (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: U.S. Department of Veterans Affairs (I01 BX003527, I21BX003807)
Topics: Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
Keywords: gamma-secretase, presenilin, gamma-secretase inhibitors, γ-secretase modulators, Alzheimer's disease, amyloid-beta, amyloid precursor protein, familial Alzheimer's disease, neuroinflammation, tau phosphorylation, neurofibrillary tangles, neurodegeneration
MeSH terms: Alzheimer Disease, Animals, Humans, Protease Inhibitors, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, tau Proteins, Amyloid Precursor Protein Secretases

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γ-Secretase and its modulators: Twenty years and beyond

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