Amyloid-beta and Alzheimer’s disease: the role of neprilysin-2 in amyloid-beta clearance

Abstract

Accumulation of the amyloid-beta (Aβ) peptide is a central factor in Alzheimer’s disease (AD) pathogenesis as supported by continuing evidence. This review concisely summarizes this evidence supporting a critical role for Aβ in AD before discussing the clearance of this peptide. Mechanisms of clearance of Aβ are critical for preventing pathological elevations in Aβ concentration. Direct degradation of Aβ by endopeptidases has emerged as one important pathway for clearance. Of particular interest are endopeptidases that are sensitive to the neprilysin (NEP) inhibitors thiorphan and phosphoramidon (i.e., are “NEP-like”) as these inhibitors induce a dramatic increase in Aβ levels in rodents. This review will focus on neprilysin-2 (NEP2), a NEP-like endopeptidase which cooperates with NEP to control Aβ levels in the brain. The evidence for the involvement of NEP2 in AD is discussed as well as the therapeutic relevance with regards to gene therapy and the development of molecular markers for the disease.

Hypertension and Alzheimer Disease

“…Although various Aβ peptide lengths are produced by γ-secretase, Aβ 42 and Aβ 40 are of particular interest because the additional 2 hydrophobic residues in Aβ 42 increase its ability to aggregate, providing the scaffold for oligomeric and fibrillar forms of Aβ. 2 The possible causal role of Aβ in AD is supported by the fact that a high Aβ 42 to Aβ 40 ratio is an important determinant for the onset of amyloid pathology in familial AD.…”

“…This compound, however, is poorly selective for amyloid precursor protein compared with Notch, which could be responsible for its toxicity. 2 The only alternative to a cure for AD would be prevention. It has been recently proposed that only by targeting modifiable risk factors, such as diabetes mellitus, midlife hypertension, midlife obesity, physical inactivity, depression, smoking, and low educational attainment, as much as one third of AD cases could be prevented.…”

“…1 There are 2 forms of AD: first, the familial AD represents <2% of the cases; it is inherited in an autosomal dominant pattern with symptoms typically presenting as early as 24 years of age for the most aggressive familial AD mutation identified to date, the Leu to Pro mutation at position 166 of presenilin-1. 2 The second form is the sporadic late onset AD; it is much more prevalent but develops much later clinically, usually beginning after 70 or 80 years of age. AD pathology is confirmed postmortem by the accumulation of extracellular amyloid-β (Aβ) containing plaques and intracellular neurofibrillary tau tangles in the brain.…”

Effect of Sargassum serratifolium Extracts on β-Amyloid Production

“…, (neuritic or senile plaques) (neurofibrillary tangles) (Marr and Hafez, 2014). , (beta-amyloid, A ) (Dá Mesquita et al, 2016).…”

Transmission des lésions amyloïdes de la maladie d’Alzheimer : apports des modèles animaux

“…Cette clairance peut se produire par son évacuation à travers la paroi vasculaire vers la circulation, sa phagocytose par la microglie ou sa dégradation protéolytique (Miners et al 2011) par de multiples enzymes telles que la néprilysine et l'enzyme dégradant l'insuline (Marr & Hafez, 2014). Une sur-production d'Ab peut aussi contribuer à son accumulation dans le cerveau, comme c'est le cas dans certaines MA d'origine génétique (Mawuenyega et al 2010).…”