Abstract
One of the most critical pathological features of Alzheimer’s disease (AD) is the accumulation of β-amyloid (Aβ) peptides that form extracellular senile plaques in the brain. Aβ is derived from β-amyloid precursor protein (APP) through sequential cleavage by β- and γ-secretases. γ-secretase is a high molecular weight complex minimally composed of four components: presenilins (PS), nicastrin, anterior pharynx defective 1 (APH-1), and presenilin enhancer 2 (PEN-2). In addition to APP, γ-secretase also cleaves many other type I transmembrane (TM) protein substrates. As a crucial enzyme for Aβ production, γ-secretase is an appealing therapeutic target for AD. Here, we summarize current knowledge on the structure and function of γ-secretase, as well as recent progress in developing γ-secretase targeting drugs for AD treatment.
Highlights
Alzheimer’s disease (AD) is the most prevalent aging associated neurodegenerative disorder, afflicting approximately 10% of the population over age 65 and 30–50% of the population over age 85
Because the clinicopathological features of familial early-onset AD (FAD) are apparently indistinguishable from sporadic AD cases, great efforts have been devoted to studying these FAD linked genes and significant progress has been made to reveal mechanisms underlying AD pathogenesis
Senile plaques are largely comprised of variously sized Aβ peptides, where most peptides are represented by Aβ40 and the more deleterious Aβ42 species (Glenner and Wong, 1984; Masters et al, 1985; McColl et al, 2012)
Summary
Alzheimer’s disease (AD) is the most prevalent aging associated neurodegenerative disorder, afflicting approximately 10% of the population over age 65 and 30–50% of the population over age 85. SUBUNITS OF THE γ-SECRETASE COMPLEX AND THEIR ASSEMBLY “γ-secretase” was first used to describe the proteolytic activity that cleaves APP within the transmembrane (TM) domain (Haass and Selkoe, 1993).
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