Presenilin 1 (Ps1) is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.
Presenilin-1 (PS1), encoded by the psen1 gene on chromosome 14q24.2, is a 467-amino acid multi-pass transmembrane protein that serves as the catalytic subunit of the gamma-secretase complex. This aspartyl protease complex cleaves over 100 type I transmembrane substrates, most notably app (app to generate amyloid-beta ([Aβ) peptides, and Notch receptors, which are essential for cell fate determination during development.[1] [2]
Mutations in psen1 are the most common cause of early-onset familial alzheimers (FAD), accounting for approximately 70% of autosomal dominant AD cases. Over 450 [3]
pathogenic psen1 variants have been identified — more than in any other gene associated with AD — with disease onset typically between ages 25–60, often decades earlier than [4]
sporadic AD.[5] The vast majority of these mutations [6]
cause a loss of gamma-secretase's precision cleavage (processivity), shifting amyloid-beta production toward longer, more aggregation-prone Aβ42/43 peptides relative to shorter Aβ38/40 [7]
species.[2:1] [8]
PS1 is a polytopic membrane protein with nine transmembrane domains (TMDs) and a large cytoplasmic loop between TMD6 and TMD7: [5:1]
PS1 functions within a heterotetrameric complex consisting of: [9]
Cryo-EM structures of the gamma-secretase complex (resolved to ~2.6 Å with substrate bound) have revealed how the complex accommodates substrates within a water-filled intramembrane chamber and how FAD mutations distort the substrate binding channel.[3:1] [10]
During gamma-secretase assembly, PS1 undergoes autocatalytic endoproteolysis within the large cytoplasmic loop (between TMD6 and TMD7), generating a ~28 kDa N-terminal fragment (NTF) and ~18 kDa C-terminal fragment (CTF). These fragments remain tightly associated as a heterodimer within the active complex. Only endoproteolyzed PS1 is catalytically active. The stoichiometry of the mature complex is 1:1:1:1 (PS1-NTF/CTF:Nicastrin:APH-1:PEN-2). [11]
PS1-containing gamma-secretase performs regulated intramembrane proteolysis (RIP) of type I transmembrane proteins. The cleavage of app proceeds through a well-defined sequence:[2:2] [12]
Two major product lines exist: [13]
PS1 also has functions independent of its role in gamma-secretase:[7:1] [14]
Over 450 psen1 mutations have been identified in FAD families worldwide. Key features:5,8 [15]
Stalled enzyme-substrate complexes: A 2025 study revealed that FAD mutations lead to stabilized gamma-secretase/substrate complexes that accumulate at synapses and trigger synaptic loss independently of amyloid-beta production, representing a novel pathogenic mechanism beyond the canonical amyloid hypothesis.[14:1] [16]
| Mutation | Age of Onset | Prevalence | Notes | [17]
|----------|-------------|------------|-------| [18]
| E280A | ~49 years | Largest FAD kindred (~6000 carriers, Antioquia, Colombia) | DIAN and Alzheimer's Prevention Initiative trial target | [19]
| A431E | 25–35 years | Mexican families | Among the most aggressive PSEN1 mutations | [20]
| H163R | 45–55 years | European families | Common in Scandinavian populations | [21]
| M146L/V | 38–48 years | Multiple ethnicities | Well-characterized biochemical effects | [22]
| L166P | 24–35 years | European | Near-complete loss of processivity; among earliest onset known | [23]
| A246E | 50–60 years | Multiple families | Founder mutation in some populations | [24]
While the primary phenotype is Alzheimer's dementia, some PSEN1 mutations cause atypical presentations:[12:1] [25]
GSMs shift Aβ production from longer species (Aβ42) toward shorter species (Aβ38/37) without affecting total Aβ levels or Notch processing. This approach directly addresses the processivity defect caused by PSEN1 mutations:[10:1] [26]
A 2024 proof-of-concept study demonstrated that AAV9-mediated delivery of wild-type human PSEN1 can rescue gamma-secretase function in four different lines of Psen-mutant mice, reducing Aβ42/40 ratios and improving synaptic function — establishing gene replacement as a potential therapeutic strategy for FAD carriers.[13:1] [27]
Allen Human Brain Atlas: Presenilin-1 expression search
Allen Mouse Brain Atlas: Presenilin-1 search
Allen Cell Type Atlas: Transcriptomic cell type reference
BrainSpan Developmental Transcriptome: Presenilin-1 developmental expression
The study of Presenilin 1 (Ps1) has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development. [28]
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.
[De Strooper B (2003). Aph-1, Pen-2, and nicastrin with presenilin generate an active gamma-secretase complex](https://doi.org/10.1016/S0896-6273(03). [neurons. 2003. ↩︎
Szaruga M, Munteanu B, Lisber S, et al. (2017). Alzheimer's-causing mutations shift Aβ length by destabilizing γ-secretase-Aβn interactions. Cell, 170(3):443-456. DOI. 2017. ↩︎ ↩︎ ↩︎ ↩︎
Bai XC, Yan C, Yang G, et al. (2015). An atomic structure of human γ-secretase. Nature, 525(7568):212-217. DOI. 2015. ↩︎ ↩︎
Bentahir M, Nyabi O, Bhatt D, et al. (2006). Presenilin clinical mutations can affect gamma-secretase activity by different mechanisms. Journal of Neurochemistry, 96(3):732-742. DOI. 2006. ↩︎
Sherrington R, Rogaev EI, Liang Y, et al. (1995). Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's Disease. Nature, 375(6534):754-760. DOI. 1995. ↩︎ ↩︎
Sun L, Zhou R, Yang G, et al. (2017). Analysis of 138 pathogenic mutations in. psen1 on the in vitro production of Aβ42 and Aβ40 peptides by γ-secretase. PNAS, 114(4):E476-E485. DOI. 2017. ↩︎
Tu H, Nelson O, Bhatt A, et al. (2006). Presenilins form ER Ca2+ leak channels, a function disrupted by familial Alzheimer's Disease-linked mutations. Cell, 126(5):981-993. DOI. 2006. ↩︎ ↩︎
Lee JH, Yu WH, Kumar A, et al. (2010). Lysosomal proteolysis and autophagy require presenilin 1 and are disrupted by Alzheimer-related PS1 mutations. Cell, 141(7):1146-1158. DOI. 2010. ↩︎
Coen K, Flannagan RS, Baron S, et al. (2012). Lysosomal calcium homeostasis defects, not proton pump defects, cause endo-lysosomal dysfunction in PSEN-deficient cells. Journal of Cell Biology, 198(1):23-35. DOI. 2012. ↩︎ ↩︎
Kretner B, et al. (2016). Generation and deposition of Aβ43 by the virtually inactive. psen1 L435F mutant contradicts the presenilin loss-of-function hypothesis of Alzheimer's Disease. EMBO Molecular Medicine, 8(5):458-465. DOI. 2016. ↩︎ ↩︎
Romero-Molina C, et al. (2023). Presenilin-1 mutations: clinical phenotypes beyond Alzheimer''s Disease. International Journal of Molecular Sciences, 24(9):8417. DOI: 10.3390/ijms24098417). 2023. ↩︎ ↩︎
Bhatt A, et al. (2024). Proof-of-concept presenilin-based gene therapy targets early-onset Alzheimer's Disease carrying PSEN mutations. Brigham and Women's Hospital/Harvard Medical School. Summary. 2024. ↩︎ ↩︎
Bhatt A, et al. (2025). Presenilin-1 familial Alzheimer mutations impair γ-secretase cleavage of. app through stabilized enzyme-substrate complex formation. Biomolecules, 15(7):955. DOI: 10.3390/biom15070955). 2025. ↩︎ ↩︎
Veugelen S, et al. (2025). Identification of presenilin mutations that have sufficient gamma-secretase proteolytic activity to mediate Notch signaling but disrupt organelle and neuronal health. PMC. PMC: 12184874. 2025. ↩︎
-. NCBI Gene: PSEN1. ↩︎
-. OMIM: 104311. ↩︎
-. GeneCards: PSEN1. ↩︎