γ-Secretase and its modulators: Twenty years and beyond

NEUROSCIENCE LETTERS

卷:701

Review

Xia, Weiming^1,2 

[1] Edith Nourse Rogers Mem Vet Hosp, Geriatr Res Educ Clin Ctr, Bldg 70,Room 202, Bedford, MA 01730 USA

[2] Boston Univ, Sch Med, Dept Pharmacol & Expt Therapeut, Boston, MA 02118 USA

关键词: Alzheimer;    Secretase;    Modulator;    Neuroinflammation;   

DOI  :  10.1016/j.neulet.2019.02.011

来源: Elsevier

【 摘 要 】

Twenty years ago, Wolfe, Xia, and Selkoe identified two aspartate residues in Alzheimer's presenilin protein that constitute the active site of the gamma-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 beta-secretase and gamma-secretase/presenilin generate amyloid beta protein (A beta), the major component of pathological hallmark, neuritic plaques, in brains of AD patients. Therapeutic strategies centered on targeting gamma-secretase/presenilin to reduce amyloid were implemented and led to several high profile clinical trials. This review article focuses on the studies of gamma-secretase and its inhibitors/modulators since the discovery of presenilin as the gamma-secretase. While a lack of complete understanding of presenilin biology renders failure of clinical trials, the lessons learned from some gamma-secretase modulators, while premature for human testing, provide new directions to develop potential therapeutics. Imbalanced A beta homeostasis is an upstream event of neurodegenerative processes. Exploration of gamma-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.

【 授权许可】

Free