期刊
FRONTIERS IN AGING NEUROSCIENCE
卷 11, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fnagi.2019.00244
关键词
amyloid precursor protein; matrix metalloproteinases; eta-secretase; meprin-beta; legumain; rhomboid-like protein-4; caspase; neurodegenerative disease
资金
- CNRS
- Aix-Marseille Universite
- DHUNE Centre of Excellence
- CoEN
- Fondation Plan Alzheimer
- France Alzheimer
- ANR
- Excellence Initiative of Aix-Marseille Universite - A*MIDEX, a French Investissements d'Avenir program through the ICN Ph.D. program
- French National Research Agency (ANR)
- MAD5, second Investissements d'Avenir program
- Excellence Initiative of Aix-Marseille Universite - A*MIDEX, a French Investissements d'Avenir program through the NeuroSchool
- Excellence Initiative of Aix-Marseille Universite -A*MIDEX, a French Investissements d'Avenir program
- Vaincre l'Alzheimer
Processing of amyloid beta precursor protein (APP) into amyloid-beta peptide (A beta) by beta-secretase and gamma-secretase complex is at the heart of the pathogenesis of Alzheimer's disease (AD). Targeting this proteolytic pathway effectively reduces/prevents pathology and cognitive decline in preclinical experimental models of the disease, but therapeutic strategies based on secretase activity modifying drugs have so far failed in clinical trials. Although this may raise some doubts on the relevance of beta- and gamma-secretases as targets, new APP-cleaving enzymes, including meprin-beta, legumain (delta-secretase), rhomboid-like protein-4 (RHBDL4), caspases and membrane-type matrix metalloproteinases (MT-MMPs/eta-secretases) have confirmed that APP processing remains a solid mechanism in AD pathophysiology. This review will discuss recent findings on the roles of all these proteinases in the nervous system, and in particular on the roles of MT-MMPs, which are at the crossroads of pathological events involving not only amyloidogenesis, but also inflammation and synaptic dysfunctions. Assessing the potential of these emerging proteinases in the Alzheimer's field opens up new research prospects to improve our knowledge of fundamental mechanisms of the disease and help us establish new therapeutic strategies.
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