Secretases Related to Amyloid Precursor Protein Processing

Abstract

Alzheimer’s disease (AD) is a common neurodegenerative disease whose prevalence increases with age. An increasing number of findings suggest that abnormalities in the metabolism of amyloid precursor protein (APP), a single transmembrane aspartic protein that is cleaved by β- and γ-secretases to produce β-amyloid protein (Aβ), are a major pathological feature of AD. In recent years, a large number of studies have been conducted on the APP processing pathways and the role of secretion. This paper provides a summary of the involvement of secretases in the processing of APP and the potential drug targets that could provide new directions for AD therapy.

Meta-analysis and systematic review of peripheral platelet-associated biomarkers to explore the pathophysiology of alzheimer's disease

“…Our meta-analysis found no significant difference in platelet PSEN-1 level between AD patients and healthy controls; this finding was different from previous study [ 25 ]. The PSEN protein encoded by PSEN-1 and PSEN-2 genes is an important component of γ-secretase [ 26 ]. Mutations in PSEN-1 gene mutation result in conformational changes, which further affect γ -secretase activity and increase the production of Aβ42 [ 26 ].…”

Amylin and Secretases in the Pathology and Treatment of Alzheimer’s Disease

“…Only when Pen-2 lyses the high molecular mass complex and presents the active aspartate residues of Psn does the structure come together as the active γ-secretase enzyme [ 75 ]. It is important to note that due to the multiplex nature of the γ-secretase complex, this protein is able to perform an array of different functions in unalike cells [ 76 ].…”

“…γ-secretase is unspecific and has many lipid-based intramembrane substrates that it targets, particularly among type I transmembrane proteins. APP was the first substrate demonstrated to be targeted by γ-secretase [ 76 ]. γ-secretase targets the c-terminal of the Aβ domain of APP after upstream processing by α- and β-secretases, releasing Aβ and APP intracellular domain (AICD) [ 27 ].…”

The Role of a Pathological Interaction between β-amyloid and Mitochondria in the Occurrence and Development of Alzheimer’s Disease

“…sAPPα известен многочисленными нейроза-щитными функциями, в частности, он противодействует токсическим эффектам Аβ [36,37]. Затем α-CTF расщепляется γ-секретазой до гидрофобного фрагмента P3 (3 кДа) и внутриклеточного домена белка-предшественника амилоида (AICD) [38]. Функциональный γ-секретазный комплекс включает в себя следующие белки: пресенилин 1 (PS-1) или пресенилин 2 (PS-2), которые относятся к каталитическому домену, а также никастрин, служащий рецептором субстрата [39], усилитель пресенилина 1 (Pen-1, или aph-1, anterior pharynx-defective 1) и усилитель пресенилина 2 (Pen-2) [40].…”

“…sAPPα is known for its numerous neuroprotective functions; in particular, it counteracts the toxic effects of Aβ [ 36 , 37 ]. Next, α-CTF is cleaved by γ-secretase to generate the hydrophobic P3 peptide (3 kDa) and intracellular domain of the amyloid precursor protein (AICD) [ 38 ]. The functional γ-secretase complex includes the following proteins: either presenilin 1 (PS-1) or presenilin 2 (PS-2), which belong to the catalytic domain; nicastrin, which serves as a substrate receptor [ 39 ]; presenilin-enhancer-1 (Pen-1, or aph-1; anterior pharynx-defective 1) and presenilin-enhancer-2 (Pen-2) [ 40 ].…”