Presenilin-1 (PSEN1) (PSEN1)

Presenilin-1 (PSEN1) is a multi-pass transmembrane protein that serves as the catalytic subunit of the gamma-secretase complex, an intramembrane aspartyl protease [1, 3, 14]. It is responsible for the final cleavage of the amyloid precursor protein (APP) into amyloid-beta (Aβ) peptides, including the highly aggregation-prone Aβ42 isoform [1, 4, 15]. Mutations in the PSEN1 gene are the most frequent cause of early-onset familial Alzheimer's disease, typically leading to an increased Aβ42/Aβ40 ratio and accelerated plaque formation [2, 10, 11]. Beyond its role in amyloidogenesis, PSEN1 is essential for the proteolytic activation of the Notch receptor, which regulates cell fate and development, as well as other substrates involved in calcium signaling and cell adhesion [2, 4, 12]. Therapeutic strategies targeting PSEN1 have primarily focused on gamma-secretase inhibitors (GSIs) and modulators (GSMs) to reduce Aβ production [6, 7, 8]. However, clinical development of GSIs for Alzheimer's has been hindered by significant safety concerns, particularly toxicities arising from the inhibition of Notch signaling and paradoxical cognitive decline [1, 6, 7].

Other names

PS-1AD3S182FADPresenilin 1ACNINV3

Presenilin-1 acts as the catalytic core of the gamma-secretase complex. Drugs targeting this molecule typically function as gamma-secretase inhibitors (GSIs) or gamma-secretase modulators (GSMs). GSIs block the proteolytic activity of the complex entirely, preventing the cleavage of APP and other substrates like Notch. GSMs shift the cleavage site of APP to produce shorter, non-toxic Amyloid-beta peptides without significantly affecting Notch signaling [1, 6, 7].