```mermaid
flowchart TD
PSEN["PRESENILIN<br/>Gene/Protein"]
GAMMA["gamma-Secretase<br/>Complex"]
APP["Amyloid Precursor<br/>Protein (APP)"]
ABETA["Amyloid-beta<br/>Peptides"]
PLAQUES["Amyloid<br/>Plaques"]
FAD["Familial<br/>Alzheimer's Disease"]
AD["Alzheimer's<br/>Disease"]
DEMENTIA["Dementia<br/>Phenotype"]
NEURODEGENERATION["Neurodegeneration<br/>Process"]
NOTCH["Notch<br/>Signaling"]
CALCIUM["Calcium<br/>Homeostasis"]
TAUOPATHY["Tauopathy<br/>Pathology"]
PD["Parkinson's<br/>Disease"]
ALS["Amyotrophic Lateral<br/>Sclerosis"]
AGING["Cellular<br/>Aging"]
PSEN -->|"forms"| GAMMA
GAMMA -->|"cleaves"| APP
APP -->|"produces"| ABETA
ABETA -->|"aggregates"| PLAQUES
PSEN -->|"mutations cause"| FAD
FAD -->|"leads to"| AD
AD -->|"manifests as"| DEMENTIA
PLAQUES -->|"triggers"| NEURODEGENERATION
PSEN -->|"regulates"| NOTCH
PSEN -->|"disrupts"| CALCIUM
CALCIUM -->|"dysregulation"| NEURODEGENERATION
PSEN -->|"expressed in"| TAUOPATHY
PSEN -->|"associated with"| PD
PSEN -->|"associated with"| ALS
PSEN -->|"regulates"| AGING
AGING -->|"contributes to"| NEURODEGENERATION
<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">Presenilin-1</th>
</tr>
<tr> [@ref]
<td class="label">Gene</td> [@refa]
<td>[PSEN1](/entities/psen1)</td> [@refb]
</tr> [@refc]
<tr> [@refd]
<td class="label">UniProt</td> [@refe]
<td><a href="https://www.uniprot.org/uniprot/P49768" target="_blank">P49768</a></td> [@page2026]
</tr> [@psen]
<tr> [@alzheimers]
<td class="label">PDB Structures</td> [@amyloidbetaproteinsamyloidbeta]
<td><a href="https://www.rcsb.org/structure/5A63" target="_blank">5A63</a>, <a href="https://www.rcsb.org/structure/6IDF" target="_blank">6IDF</a>, <a href="https://www.rcsb.org/structure/6IYC" target="_blank">6IYC</a></td> [@gammasecretase]
</tr> [@psena]
<tr> [@alzheimersa]
<td class="label">Molecular Weight</td> [@amyloidbetaproteinsamyloidbetaa]
<td>52 kDa</td> [@gammasecretasea]
</tr> [@amyloidbeta]
<tr> [@betasecretase]
<td class="label">Localization</td>
<td>Endoplasmic reticulum, Golgi, cell membrane ([gamma-secretase](/entities/gamma-secretase) complex)</td>
</tr>
<tr>
<td class="label">Protein Family</td>
<td>Presenilin family (intramembrane aspartyl protease)</td>
</tr>
<tr>
<td class="label">Diseases</td>
<td>[Alzheimer's Disease](/diseases/alzheimers), [Frontotemporal Dementia](/diseases/ftd)</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">ALS</a>, <a href="/wiki/alzheimer" style="color:#ef9a9a">ALZHEIMER</a>, <a href="/wiki/alzheimer's-disease" style="color:#ef9a9a">ALZHEIMER'S DISEASE</a>, <a href="/wiki/aging" style="color:#ef9a9a">Aging</a>, <a href="/wiki/als" style="color:#ef9a9a">Als</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">508 edges</a></td>
</tr>
</table>
[Presenilin 1](/proteins/presenilin-1) 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) is a 467-amino acid, ~50 kDa multi-pass transmembrane protein encoded by the [psen1](/genes/psen1) gene on chromosome 14q24.2. [It functions as the catalytic subunit of the γ-secretase complex, an intramembrane-cleaving protease (I-CLiP) responsible for processing over 150 type I transmembrane proteins, most notably [amyloid precursor protein ([app](/proteins/app), with over 300 pathogenic variants identified — the largest collection of disease-causing mutations in any single AD gene. [psen1](/genes/psen1) mutations account for approximately 70% of all genetically determined early-onset AD cases and typically cause disease onset between ages 30 and 60 ([Sherrington et al., 1995).
The identification of [psen1](/genes/psen1) in 1995 was a landmark event in Alzheimer's research, providing the first direct genetic link between γ-secretase activity and familial AD. The subsequent discovery that presenilin constitutes the catalytic core of γ-secretase established the molecular basis for the amyloidogenic pathway and launched intensive efforts to target this enzyme therapeutically.
Presenilin-1 is a polytopic membrane protein with nine transmembrane domains (TMDs). The protein undergoes auto-proteolytic endoproteolysis between TMD6 and TMD7 (at residues ~290–300), generating:
γ-Secretase is an obligate heterotetrameric complex assembled from four essential subunits:
| Subunit | Gene | MW | Function |
|---|---|---|---|
| Presenilin-1 (or Presenilin-2) | [psen1](/genes/psen1) / [psen2](/genes/psen2) | 52 kDa | Catalytic subunit; contains intramembrane aspartyl protease active site |
| Nicastrin (NCT) | NCSTN | 130 kDa (glycosylated) | Substrate recognition; ectodomain acts as a molecular "gatekeeper," screening substrate stubs by size |
| APH-1 (Anterior Pharynx-Defective 1) | APH1A or APH1B | 29 kDa | Scaffold protein; stabilizes complex assembly with seven TMDs |
| PEN-2 (Presenilin Enhancer 2) | PSENEN | 12 kDa | Triggers presenilin endoproteolysis and activates the mature complex |
All four subunits are required for enzymatic activity. The complex assembles in the endoplasmic reticulum, matures in the Golgi, and localizes to the cell surface, endosomes, and lysosomes. Humans express two presenilin paralogs (PS1 and PS2) and two APH-1 paralogs (APH-1A and APH-1B), generating at least four distinct γ-secretase complexes with overlapping but non-identical substrate preferences and tissue distributions.
High-resolution cryo-EM structures have been transformative for understanding γ-secretase:
γ-Secretase performs sequential, processive cleavage of the [app](/proteins/app) C-terminal fragments (C99 from [bace1-protein](/proteins/bace1-protein) β-cleavage, or C83 from α-secretase cleavage):
Two major product lines exist:
γ-Secretase-mediated S3 cleavage of Notch receptors (Notch-1 through Notch-4, following ADAM10/TACE S2 cleavage) releases the Notch intracellular domain (NICD), which translocates to the nucleus and activates target gene transcription through the CSL (CBF1/Su(H)/Lag-1) transcription factor complex. Notch signaling is essential for:
Beyond APP and Notch, γ-secretase processes numerous type I transmembrane proteins, including:
| Mutation | Onset Age | Population/Notes |
|---|---|---|
| E280A ("Paisa") | ~44 years | Largest known FAD kindred (~5,000 carriers in Antioquia, Colombia); subject of the API (Alzheimer's Prevention Initiative) [crenezumab and [lecanemab](/therapeutics/lecanemab) prevention trials |
| A246E | ~55 years | One of the first PSEN1 mutations discovered |
| L166P | ~25 years | Among the earliest onset; severe loss of γ-secretase trimming function |
| H163R | ~50 years | First Finnish mutation; variable phenotype |
| A431E ("Jalisco") | ~42 years | Large Mexican kindred with cotton wool plaques |
| M146L/V | ~40–45 years | Among the most common PSEN1 mutations |
| G206A | ~58 years | "Cherry blossom" kindred; spastic paraparesis phenotype |
| Δexon 9 | ~45 years | Large Finnish pedigree; cotton wool plaques with spastic paraparesis |
Emerging evidence challenges the simple "Aβ42 gain-of-toxic-function" model of PSEN1 mutations. The presenilin loss-of-function hypothesis proposes that many FAD mutations cause partial loss of γ-secretase catalytic function, which contributes to neurodegeneration through mechanisms beyond just altered Aβ42/Aβ40 ratios:
This debate — gain-of-function (toxic Aβ42) vs. loss-of-function (impaired presenilin biology) — remains one of the most important unresolved questions in AD research ([Bhatt et al., 2020).
While most PSEN1 mutation carriers develop typical amnestic AD, a subset present with atypical phenotypes:
GSIs block all γ-secretase substrates and have uniformly failed in clinical trials:
GSMs represent a more promising approach — they shift the γ-secretase cleavage profile toward shorter [amyloid-beta](/proteins/amyloid-beta) species (Aβ37, Aβ38) without inhibiting overall γ-secretase activity or blocking Notch processing:
Proof-of-concept studies have demonstrated that delivering a functional copy of the PSEN1 gene via AAV vectors can restore normal γ-secretase activity in cells carrying FAD mutations. This approach is being explored particularly for the large Colombian E280A kindred ([Bhatt et al., 2024).
Emerging strategies aim to block APP-specific γ while preserving Notch and other substrate cleavage, exploiting structural differences in how γ-secretase engages different substrates.
[Presenilin-2](/entities/psen2) (PS2), encoded by [psen2](/genes/psen2) on chromosome 1q42.13, shares ~67% amino acid identity with PS1 and can substitute as the catalytic subunit in γ-secretase complexes. However, PS2-containing complexes have lower catalytic activity and different subcellular localization (enriched in late endosomes/lysosomes). [psen2](/genes/psen2) mutations are rare causes of FAD (~40 pathogenic variants, vs. >300 for PSEN1), typically with later onset (45–88 years) and more variable penetrance. The "Volga German" [psen2](/genes/psen2) N141I mutation is the most well-characterized.
The study of Presenilin 1 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.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.
The following diagram shows the key molecular relationships involving Presenilin-1 discovered through SciDEX knowledge graph analysis: