Presenilin-1 (PS1)

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Presenilin-1 (PS1)

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Introduction

[Presenilin 1](/proteins/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.

Overview

Presenilin-1 (PS1), encoded by the [psen1](/genes/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](/proteins/gamma-secretase) complex. This aspartyl protease complex cleaves over 100 type I transmembrane substrates, most notably [app](/genes/app) ([app](/genes/app) to generate [amyloid-beta](/proteins/amyloid-beta) ([Aβ) peptides, and Notch receptors, which are essential for cell fate determination during development.[@strooper2003] [@szaruga2017]

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Introduction

[Presenilin 1](/proteins/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.

Overview

Presenilin-1 (PS1), encoded by the [psen1](/genes/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](/proteins/gamma-secretase) complex. This aspartyl protease complex cleaves over 100 type I transmembrane substrates, most notably [app](/genes/app) ([app](/genes/app) to generate [amyloid-beta](/proteins/amyloid-beta) ([Aβ) peptides, and Notch receptors, which are essential for cell fate determination during development.[@strooper2003] [@szaruga2017]

Mutations in [psen1](/genes/psen1) are the most common cause of early-onset familial [alzheimers](/diseases/alzheimers-disease) (FAD), accounting for approximately 70% of autosomal dominant AD cases. Over 450 [@bai2015]
pathogenic [psen1](/genes/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 [@bentahir2006]
sporadic AD.[@sherrington1995] The vast majority of these mutations [@sun2017]
cause a loss of [gamma-secretase](/proteins/gamma-secretase)'s precision cleavage (processivity), shifting [amyloid-beta](/proteins/amyloid-beta) production toward longer, more aggregation-prone Aβ42/43 peptides relative to shorter Aβ38/40 [@tu2006]
species.[@szaruga2017] [@lee2010]

Structure

Protein Topology

PS1 is a polytopic membrane protein with nine transmembrane domains (TMDs) and a large cytoplasmic loop between TMD6 and TMD7: [@sherrington1995]

The N-terminus and C-terminus reside in the cytoplasm
TMD6 and TMD7 harbor the two catalytic aspartate residues (Asp257 and Asp385) that form the active site of the [gamma-secretase](/proteins/gamma-secretase) aspartyl protease
The large intracellular loop (~110 amino acids) undergoes regulated endoproteolysis during [gamma-secretase](/proteins/gamma-secretase) complex maturation
TMD1–6 and TMD7–9 form two structural halves that create a water-filled intramembrane cavity for substrate access

Gamma-Secretase Complex

PS1 functions within a heterotetrameric complex consisting of: [@coen2012]

Presenilin-1 (or [Presenilin-2): Catalytic subunit — provides the aspartyl protease activity

Nicastrin: Substrate recognition and gating — its ectodomain acts as a steric gatekeeper, admitting only substrates whose ectodomains have been previously shed

APH-1 (anterior pharynx-defective 1): Scaffolding and stabilization during complex assembly

PEN-2 (presenilin enhancer 2): Triggers PS1 endoproteolysis and activation; required for catalytic maturation

Cryo-EM structures of the [gamma-secretase](/proteins/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.[@bai2015] [@kretner2016]

Endoproteolysis and Activation

During [gamma-secretase](/proteins/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). [@alzforum]

Normal Function

Gamma-Secretase Activity: Sequential Cleavage

PS1-containing [gamma-secretase](/proteins/gamma-secretase) performs regulated intramembrane proteolysis (RIP) of type I transmembrane proteins. The cleavage of [app](/genes/app) proceeds through a well-defined sequence:[@szaruga2017] [@romeromolina2023]

ε-cleavage (initial endopeptidase cut): Occurs at the membrane-cytoplasm boundary at Aβ48 or Aβ49 position, releasing the [app](/genes/app) intracellular domain (AICD)

ζ-cleavage (first tripeptide trimming): Aβ49→46 or Aβ48→45

γ-cleavage (successive tripeptide trimming): Continues as Aβ46→43→40 or Aβ45→42→38, with each step releasing a tri- or tetrapeptide

The final released [amyloid-beta](/proteins/amyloid-beta) species depends on the efficiency of this processivity — FAD mutations reduce processivity, causing premature substrate release at longer (more pathogenic) species

Two major product lines exist: [@bhatt2024]

Aβ49 → 46 → 43 → 40 → 37 (the predominant pathway, producing shorter, less pathogenic species)
Aβ48 → 45 → 42 → 38 (produces Aβ42, the more aggregation-prone species)

Major Substrates

[app](/genes/app): Generates [amyloid-beta](/proteins/amyloid-beta) peptides of varying lengths (Aβ37–43)
Notch: Cleavage releases the Notch intracellular domain (NICD), which translocates to the nucleus to regulate transcription of HES/HEY target genes — essential for neural development, adult neurogenesis, and immune cell differentiation
E-cadherin: Cell adhesion molecule; cleavage modulates cell-cell contacts
ErbB4: Receptor tyrosine kinase; cleavage releases signaling domain
[lrp1](/genes/lrp1), CD44, N-cadherin, DCC, p75-NTR, and >90 other substrates

Gamma-Secretase-Independent Functions

PS1 also has functions independent of its role in [gamma-secretase](/proteins/gamma-secretase):[@tu2006] [@bhatt2025]

ER calcium regulation: PS1 functions as an ER calcium leak channel; FAD mutations reduce this function, increasing ER calcium stores and sensitizing [neurons](/entities/neurons) to calcium-dependent excitotoxicity
Wnt/β-catenin signaling: PS1 interacts with β-catenin and [gsk3-beta](/mechanisms/gsk3-beta), modulating Wnt signaling independently of Notch processing
[autophagy](/mechanisms/autophagy-lysosome-neurodegeneration)/lysosomal function: PS1 is required for proper acidification of lysosomes and autophagosomes via its role in targeting the v-ATPase proton pump; FAD mutations impair lysosomal pH regulation and autophagic flux[@coen2012]
Protein trafficking: Facilitates transport of proteins through the ER-Golgi secretory pathway

Role in Alzheimer's Disease

Pathogenic Mutations

Over 450 [psen1](/genes/psen1) mutations have been identified in FAD families worldwide. Key features:5,8</a> [@veugelen2025]

Predominantly missense mutations: Single amino acid substitutions affecting [gamma-secretase](/proteins/gamma-secretase) processivity
Loss-of-processivity mechanism: Rather than increasing total [amyloid-beta](/proteins/amyloid-beta), most mutations reduce the efficiency of sequential tripeptide trimming, leading to premature release of longer Aβ42/43 before it can be trimmed to Aβ38/40[@szaruga2017]
Elevated Aβ42/40 ratio: The ratio of Aβ42 to Aβ40 is the key pathogenic metric; even modest increases (1.5–2 fold) dramatically accelerate amyloid nucleation and plaque formation
Complete penetrance: Virtually all carriers develop AD, with predictable age of onset for specific mutations
Variable onset age: Different mutations cause onset from age 24 (L166P) to age 65 (some partial loss-of-function variants), correlating inversely with the degree of gamma

Stalled enzyme-substrate complexes: A 2025 study revealed that FAD mutations lead to stabilized [gamma-secretase](/proteins/gamma-secretase)/substrate complexes that accumulate at synapses and trigger synaptic loss independently of [amyloid-beta](/proteins/amyloid-beta) production, representing a novel pathogenic mechanism beyond the canonical amyloid hypothesis.[@bhatt2025] [@alzheimers]

Notable Mutations

| Mutation | Age of Onset | Prevalence | Notes | [@gammasecretase]
|----------|-------------|------------|-------| [@psen]
| E280A | ~49 years | Largest FAD kindred (~6000 carriers, Antioquia, Colombia) | DIAN and Alzheimer's Prevention Initiative trial target | [@app]
| A431E | 25–35 years | Mexican families | Among the most aggressive PSEN1 mutations | [@amyloidbeta]
| H163R | 45–55 years | European families | Common in Scandinavian populations | [@bace]
| M146L/V | 38–48 years | Multiple ethnicities | Well-characterized biochemical effects | [@dianstudy]
| L166P | 24–35 years | European | Near-complete loss of processivity; among earliest onset known | [@amyloid]
| A246E | 50–60 years | Multiple families | Founder mutation in some populations | [@ncbi]

Clinical Phenotype Beyond AD

While the primary phenotype is Alzheimer's dementia, some PSEN1 mutations cause atypical presentations:[@romeromolina2023] [@uniprot]

Spastic paraparesis: Seen with mutations causing cotton wool plaques (e.g., Δexon 9 deletion)
Frontotemporal Dementia-like presentation: Some mutations mimic behavioral variant FTD
Lewy body pathology: Co-occurring [alpha-synuclein](/proteins/alpha-synuclein) pathology with some mutations
Cerebellar ataxia: Particularly with mutations near TMD1 and TMD2
Seizures: Myoclonus and generalized tonic-clonic seizures, particularly with early-onset mutations

Animal Models

PS1-M146V knock-in mice: Show increased Aβ42/40 ratio, enhanced ER calcium release, and accelerated amyloid pathology when crossed with [app](/genes/app) transgenics
5xFAD mice ([app](/genes/app)/PS1 double transgenic): Carry 3 [app](/genes/app) and 2 PSEN1 mutations; develop aggressive amyloid pathology by 2 months; widely used for preclinical drug testing
PS1 knockout mice: Lethal perinatally due to Notch signaling failure; demonstrate essential developmental role
Conditional PS1/PS2 double knockout mice: Develop progressive neurodegeneration and memory impairment without amyloid pathology, supporting PS1 loss-of-function as independently pathogenic

Therapeutic Targeting

Gamma-Secretase Inhibitors (Failed)

Semagacestat: Failed Phase III trial (2010) — caused cognitive worsening, skin cancer, and GI toxicity due to Notch inhibition
Avagacestat: Also failed — similar Notch-mediated toxicity and paradoxical worsening
The failure of GSIs established that non-selective gamma-secretase inhibition is not viable for AD treatment

Gamma-Secretase Modulators (Promising)

GSMs shift [Aβ](/proteins/amyloid-beta) 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:[@kretner2016] [@omim]

E2012: First-generation GSM; demonstrated proof-of-concept Aβ42 lowering
BPN-15606: Potent second-generation GSM in clinical development
NSAIDs (ibuprofen, sulindac sulfide): Original GSMs discovered incidentally; weak but validated the mechanism

Gene Therapy

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.[@bhatt2024] [@alzforuma]

Anti-Amyloid Immunotherapy

[lecanemab](/therapeutics/lecanemab) and [donanemab](/therapeutics/donanemab) target downstream Aβ pathology and are being evaluated in FAD carriers
The DIAN-TU ([dian-study](/entities/dian-study) — Trials Unit) tests therapies specifically in PSEN1/[psen2](/genes/psen2)/APP mutation carriers

Brain Atlas Resources

Allen Human Brain Atlas: [Presenilin-1 expression search](https://human.brain-map.org/microarray/search/show?search_term=Presenilin-1)
Allen Mouse Brain Atlas: [Presenilin-1 search](https://mouse.brain-map.org/search/index.html?query=Presenilin-1)
Allen Cell Type Atlas: [Transcriptomic cell type reference](https://portal.brain-map.org/atlases-and-data/rnaseq)
BrainSpan Developmental Transcriptome: [Presenilin-1 developmental expression](https://www.brainspan.org/rnaseq/search/index.html?search_term=Presenilin-1)
[Researchers Index — All researchers](/genes/ar)
[Diseases Index — Disease overview pages](/companies/overview)

External Links

[Google Scholar](https://scholar.google.com) — Publications
[PubMed](https://pubmed.ncbi.nlm.nih.gov) — Biomedical literature

Background

The study of [Presenilin 1](/proteins/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. [@genecards]

Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.

References

[Unknown, De Strooper B (2003). Aph-1, Pen-2, and nicastrin with presenilin generate an active gamma-secretase complex (2003)](https://doi.org/10.1016/S0896-6273(03)

[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)](https://doi.org/10.1016/j.cell.2017.07.004)

[Bai XC, Yan C, Yang G, et al., (2015). An atomic structure of human γ-secretase. Nature, 525(7568):212-217. [DOI (2015)](https://doi.org/10.1038/nature14892)

[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)](https://doi.org/10.1073/pnas.0608332104)

[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)](https://doi.org/10.1073/pnas.1619574114)

[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)](https://doi.org/10.1016/j.cell.2006.06.059)

[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)](https://doi.org/10.1016/j.cell.2010.05.008)

[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)](https://doi.org/10.1038/375754a0)

[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)](https://doi.org/10.1074/jbc.M113.530907)

[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)](https://doi.org/10.1038/emboj.2012.79)

Unknown, Alzforum PSEN1 database. PSEN1 Mutations — Alzforum (n.d.)

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)

Unknown, - alzheimers — Primary disease caused by PSEN1 mutations (n.d.)

Unknown, - gamma-secretase — Protease complex containing PS1 (n.d.)

Unknown, - psen2 — Homologous catalytic subunit (n.d.)

Unknown, - app — Major gamma-secretase substrate (n.d.)

Unknown, - amyloid-beta — Pathogenic product of app-protein cleavage (n.d.)

Unknown, - bace1 — Beta-secretase; upstream APP cleavage (n.d.)

Unknown, - dian-study — Clinical trials in PSEN mutation carriers (n.d.)

Unknown, - [Amyloid Cascade Hypothesis] — Theoretical framework## External Links (n.d.)

-, NCBI Gene: PSEN1 (n.d.)

-, UniProt: P49768 (PS1) (n.d.)

-, OMIM: 104311 (n.d.)

-, Alzforum PSEN1 Mutations (n.d.)

-, GeneCards: PSEN1 (n.d.)

Pathway Diagram

Mermaid diagram (expand to render)

Pathway Diagram

The following diagram shows the key molecular relationships involving Presenilin-1 (PS1) discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

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📊 Evidence Profile Foundational

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Outgoing

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📗 Cite This Artifact

Presenilin-1 (PS1)

Introduction

Overview

Introduction

Overview

Structure

Protein Topology

Gamma-Secretase Complex

Endoproteolysis and Activation

Normal Function

Gamma-Secretase Activity: Sequential Cleavage

Major Substrates

Gamma-Secretase-Independent Functions

Role in Alzheimer's Disease

Pathogenic Mutations

Notable Mutations

Clinical Phenotype Beyond AD

Animal Models

Therapeutic Targeting

Gamma-Secretase Inhibitors (Failed)

Gamma-Secretase Modulators (Promising)

Gene Therapy

Anti-Amyloid Immunotherapy

Brain Atlas Resources

External Links

Background

References

Pathway Diagram

Pathway Diagram

💬 Discussion