| Full Name |
Presenilin 1 |
| Gene |
[PSEN1](/genes/psen1) |
| UniProt |
P49768 |
| Chromosome |
14q24.2 |
| Protein Type |
Aspartyl protease (catalytic subunit) |
| Complex |
[Gamma-secretase](/proteins/gamma-secretase) |
| Molecular Weight |
~52 kDa (467 aa) |
| Key Diseases |
[Alzheimer's Disease](/diseases/alzheimers), [FTD](/diseases/ftd) |
| M146L, A246E, L286P, PSEN1dE9 |
Presenilin-1 (PSEN1) is the catalytic aspartyl protease subunit of the gamma-secretase complex, a membrane-embedded protease that cleaves the amyloid precursor protein (APP) to generate amyloid-beta (Aβ) peptides. PSEN1 is encoded by the PSEN1 gene located on chromosome 14q24.2 (NCBI Gene ID: 5663, UniProt: P49768).
Mutations in PSEN1 are the most common cause of early-onset familial Alzheimer's disease (AD), accounting for up to 70% of autosomal dominant AD cases. Over 300 pathogenic mutations have been identified, typically causing disease onset between 30-60 years of age.
Presenilin-1 is a multipass transmembrane protein with the following structural features:
- N-terminal domain: Cytoplasmic region containing the first aspartyl active site (Asp257)
- Transmembrane domains: Nine transmembrane helices (TMD 1-9)
- C-terminal domain: Contains the second aspartyl active site (Asp385)
- Hydrophobic loops: Form the protease chamber within the membrane
The catalytic core contains two essential aspartyl residues:
- Asp257 (in TMD 6)
- Asp385 (in TMD 7)
These aspartates are conserved across presenilin homologs and are essential for proteolytic activity. They coordinate a water molecule to perform nucleophilic attack on the peptide bond.
¶ Protease Domain
The protease domain is embedded within the transmembrane region, creating a unique catalytic environment:
- Active site residues are positioned within the membrane lipid bilayer
- Substrate access is controlled by the Nicastrin subunit
- The active site can accommodate transmembrane helices of substrates
PSEN1 does not function as a standalone protease — it requires assembly into the gamma-secretase complex to acquire enzymatic activity.
| Subunit |
Gene |
Function |
| Presenilin 1 |
PSEN1 |
Catalytic aspartyl protease |
| Aph-1 |
APH1A/APH1B |
Stabilizes the complex |
| Pen-2 |
PSENEN |
Required for endoproteolysis and activation |
| Nicastrin |
NCSTN |
Substrate recognition and entry |
¶ Assembly and Trafficking
- ER Assembly: Complex assembles in the endoplasmic reticulum
- Maturation: PSEN1 undergoes autocatalytic endoproteolysis to generate N-terminal and C-terminal fragments
- Trafficking: Mature complex traffics through Golgi to plasma membrane and endosomes
- Localization: Active in lipid rafts at plasma membrane and in endocytic vesicles
The gamma-secretase cleavage mechanism:
- Substrate Recognition: Nicastrin binds the extracellular domain of substrates
- Substrate Docking: Substrate undergoes conformational changes to position transmembrane domain in the active site
- Initial Cleavage: ε-cleavage at position 49-50 (produces AICD - APP intracellular domain)
- Processive Cleavage: Sequential γ-cleavages producing Aβ40, Aβ42, Aβ43 species
- Product Release: Released Aβ peptides can diffuse into extracellular space
The gamma-secretase complex, via PSEN1, mediates the final step in amyloidogenic APP processing:
- β-Secretase Cleavage: APP is first cleaved by BACE1 to generate C99 (membrane-bound C-terminal fragment)
- Gamma-Secretase Cleavage: PSEN1 cleaves C99 within its transmembrane domain:
- ε-cleavage at positions 49-50 → produces AICD (APP Intracellular Domain)
- γ-cleavage at positions 40-43 → produces Aβ peptides of varying lengths
- Aβ Species: Primary products are Aβ40 (~90%) and Aβ42 (~10%), with smaller amounts of Aβ43
The ratio of Aβ42 to Aβ40 is critical:
- Aβ42 aggregates more rapidly and is the primary component of amyloid plaques
- FAD mutations typically shift the ratio toward longer, more aggregation-prone species (Aβ42/Aβ43)
- This increase in Aβ42/43 is believed to initiate the amyloid cascade
Gamma-secretase cleaves over 100 type I transmembrane substrates:
- Notch receptors — critical for development, cell fate, and synaptic plasticity
- ErbB family — growth factor receptor signaling
- Cadherins — cell-cell adhesion
- LDL receptor family — lipid metabolism and cholesterol transport
- Ephrin receptors — neuronal guidance
- Synaptic proteins — including synaptic adhesion molecules
- Cytokine receptors — inflammatory signaling
The breadth of substrates explains the complex phenotypes seen in PSEN1 deficiency and the side effects of broad-spectrum gamma-secretase inhibitors.
Over 300 pathogenic PSEN1 mutations cause early-onset familial AD. Key characteristics:
- Age of onset: Typically 30-60 years (younger than sporadic AD)
- Penetrance: Near 100% by age 65 for most mutations
- Clinical phenotype: Progressive memory decline with classic AD features
- Neuropathology: Abundant Aβ plaques and tau neurofibrillary tangles
| Mutation |
Location |
Effect |
| M146L |
TMD 2 |
Early onset, mild phenotype |
| A246E |
Loop 6 |
Early onset |
| L286P |
TMD 6 |
Severe, very early onset |
| PSEN1dE9 |
Exon 9 deletion |
Most common, severe |
| H163R |
TMD 3 |
Typical AD phenotype |
| A431V |
TMD 8 |
Early onset |
FAD mutations affect gamma-secretase function through several mechanisms:
- Altered Cleavage Specificity: Mutations change the position of γ-cleavage sites, increasing Aβ42/43 production
- Complex Instability: Some mutations destabilize the complex assembly
- Endoplasmic Reticulum Stress: Dysregulated cleavage contributes to ER stress and unfolded protein response
- Calcium Dysregulation: PSEN1 mutations disrupt ER calcium homeostasis
- Loss of Function: Impaired cleavage of other substrates affects Notch signaling, synaptic function
- Phenotypic variability: Same mutation can cause different phenotypes in different families
- Aβ42 elevation: Mutations that cause greatest Aβ42 increase tend to have earlier onset
- Non-AD phenotypes: Some mutations cause FTD-like presentations, spastic paraparesis, or seizures
- Genetic testing: PSEN1 sequencing is essential for early-onset AD families
- Predictive testing: At-risk individuals can be tested for known family mutations
- Differential diagnosis: Helps distinguish early-onset AD from other dementias
PSEN1 mutation carriers show characteristic AD pathology:
- Amyloid plaques: Dense-core plaques with Aβ42-positive cores
- Neurofibrillary tangles: Tau protein aggregates in neurons
- Cerebral amyloid angiopathy: Aβ deposition in blood vessels
- Neuronal loss: Especially in hippocampus and cortex
PSEN1/gamma-secretase is a major therapeutic target:
- Broad-spectrum inhibitors (e.g., semagestat) failed in clinical trials due to Notch-related toxicity
- Adverse effects: Gastrointestinal toxicity, skin rash, lymphopenia, cognitive worsening
- ** Notch-independent effects**: Broader substrate effects limit therapeutic window
- Mechanism: Bind to allosteric sites to shift cleavage toward shorter Aβ species
- Advantage: Reduce Aβ42 without completely inhibiting the enzyme
- Development: Several compounds in clinical trials (e.g., avagacestat, verubecestat)
- Partial inhibition: More favorable side effect profile than direct inhibitors
- Target APP processing specifically without affecting Notch cleavage
- Currently under development
- Aβ-targeting antibodies (e.g., lecanemab, donanemab) show promise in clinical trials
- Particularly relevant for PSEN1 mutation carriers
- Early intervention may be most effective
| Partner |
Interaction Type |
Functional Effect |
| APP |
Substrate |
Primary substrate for Aβ production |
| Aph-1 |
Complex subunit |
Stabilizes complex assembly |
| Pen-2 |
Complex subunit |
Required for activation |
| Nicastrin |
Complex subunit |
Substrate recognition |
| Notch |
Substrate |
Cleaves to regulate signaling |
| BACE1 |
Sequential processing |
Upstream protease in amyloidogenesis |
| Calmodulin |
Calcium binding |
Regulates activity |
- Notch signaling: PSEN1 cleavage releases Notch intracellular domain
- Wnt signaling: Cross-talk with canonical Wnt pathway
- Calcium signaling: ER calcium homeostasis
- Protein quality control: UPR and ERAD pathways
- Cell lines: PSEN1 knockout cells, overexpression systems
- Animal models: Transgenic mice with FAD mutations (e.g., PSEN1 M146V, PSEN1dE9)
- Organoids: Human brain organoids for disease modeling
- Aβ42/40 ratio: In CSF, elevated ratio suggests PSEN1 mutation
- CSF tau: Increased in mutation carriers
- Neuroimaging: Early hippocampal atrophy on MRI
- Familial Alzheimer's disease in presenilin 1 gene. Nature, 1995.
- Presenilin mutations in familial Alzheimer's disease. Lancet Neurology, 2013.
- PSEN1 mutations and gamma-secretase function. Neuron, 2014.
- Gamma-secretase modulators in Alzheimer's disease. Nature Reviews Neurology, 2018.
- Structure of gamma-secretase. Nature, 2014.
- Presenilin and gamma-secretase: structure and function. Trends in Cell Biology, 2020.