Presenilins are aspartyl intramembrane proteases that form the catalytic core of the gamma-secretase complex.[@familial1995][@gammasecretase2010] In humans, the two principal paralogs are PSEN1 (presenilin-1) and PSEN2 (presenilin-2), both of which are central to amyloid precursor protein (APP) processing and familial Alzheimer's disease biology. Over 300 pathogenic mutations in PSEN1 and PSEN2 have been identified, accounting for the majority of early-onset familial AD cases.
Presenilins are aspartyl intramembrane proteases that form the catalytic core of the gamma-secretase complex.[@familial1995][@gammasecretase2010] In humans, the two principal paralogs are PSEN1 (presenilin-1) and PSEN2 (presenilin-2), both of which are central to amyloid precursor protein (APP) processing and familial Alzheimer's disease biology. Over 300 pathogenic mutations in PSEN1 and PSEN2 have been identified, accounting for the majority of early-onset familial AD cases.
Structure and Function
Protein Structure
Presenilins are approximately 450-500 amino acids with:
Nine transmembrane domains: Embedded in the lipid bilayer
Two aspartate residues: Located in transmembrane domains 6 and 7, essential for proteolytic activity
N-terminal and C-terminal fragments: Generated by endoproteolysis
Pen-2, APH-1, and NCT: Essential co-factors in the gamma-secretase complex
Gamma-Secretase Complex
The functional gamma-secretase complex consists of four components:
Presenilin: The catalytic subunit (PSEN1 or PSEN2)
Aph-1 (Anterior Pharynx Defective 1): Stabilizes the complex
Pen-2 (Presenilin Enhancer 2): Required for endoproteolysis and activity
Nicastrin (NCT): May serve as the substrate receptor
[Unknown, Familial Alzheimer's disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer's disease type 1 gene (1995)](https://pubmed.ncbi.nlm.nih.gov/7651536/)