APP (Amyloid Precursor Protein) is a transmembrane glycoprotein that is central to the pathogenesis of Alzheimer's disease[@goldgaber1987]. It is the source of amyloid-beta (Aβ) peptides, which accumulate in the brain as senile plaques and are considered a key driver of neurodegeneration. The APP gene was the first Alzheimer's disease gene identified, and APP mutations cause early-onset familial AD with near-complete penetrance.
APP is a type I transmembrane protein expressed in many tissues, with highest expression in the brain. It undergoes proteolytic processing by three secretases (alpha, beta, gamma) through two mutually exclusive pathways: the amyloidogenic pathway (producing Aβ) and the non-amyloidogenic pathway (precluding Aβ formation)[@selkoe1999]. The balance between these pathways is critical for Alzheimer's disease pathogenesis.
| Property |
Value |
| Gene Symbol |
APP |
| Full Name |
Amyloid Precursor Protein |
| Aliases |
A4, AD2, APPsw |
| Chromosomal Location |
21q21.3 |
| NCBI Gene ID |
351 |
| UniProt ID |
P05067 |
| Ensembl ID |
ENSG00000142192 |
| OMIM ID |
104760 |
| Gene Type |
Protein Coding |
| Gene Length |
~350 kb |
| Transcript Length |
~3.4 kb |
APP exists in multiple isoforms (695, 751, 770 amino acids) with the 770-aa form most common in brain[@selkoe1999]:
- Signal peptide (1-18): Directs protein to secretory pathway
- N-terminal extracellular domain (19-681):
- Contains E1 and E2 domains involved in dimerization and ligand binding
- Heparin-binding domain
- Copper-binding domain
- KPI domain (present in 751/770 isoforms)
- Transmembrane domain (682-703): Single alpha-helical membrane span
- Cytoplasmic domain (704-770): Contains trafficking signals and interaction partners
- YENPTY motif for endocytic trafficking
- Potential phosphorylation sites
The amyloid-beta peptide is generated from the transmembrane domain by sequential proteolysis.
APP plays important roles in synaptic physiology[@walsh2005]:
- Regulates synaptic formation and plasticity
- Modulates neurite outgrowth
- Influences long-term potentiation (LTP)
- Acts as a synaptic adhesion molecule
APP contains trafficking signals in its cytoplasmic domain[@selkoe1999]:
- Directs protein through secretory pathway
- Mediates endocytic recycling
- Interacts with adaptors (AP2, AP4, APBB1)
- Regulates its own proteolytic processing
APP has neuroprotective properties:
- Contains a growth factor-like domain
- May protect against oxidative stress
- Supports neuronal survival during development
- May have trophic functions
APP is expressed throughout the brain[@walsh2005]:
| Region |
Expression Level |
Cell Types |
| Cerebral cortex |
Highest |
Pyramidal neurons |
| Hippocampus |
Highest |
Pyramidal neurons, granule cells |
| Cerebellum |
High |
Purkinje cells |
| Basal ganglia |
Moderate |
Medium spiny neurons |
| Substantia nigra |
Moderate |
Dopaminergic neurons |
- Plasma membrane: Type I transmembrane protein
- Endoplasmic reticulum: Early secretory pathway
- Golgi apparatus: Processing and sorting
- Endosomes: Site of amyloidogenic processing
- Synaptic terminals: Presynaptic and postsynaptic
APP mutations cause familial Alzheimer's disease[@goldgaber1987]:
- Swedish mutation (KM670/671NL): Double mutation increasing Aβ production
- London mutation (V717I): Alters gamma-secretase cleavage
- Flemish mutation (A692G): Increased Aβ aggregation
- Arctic mutation (E693G): Accelerated aggregation
- APP duplications cause AD with cerebral amyloid angiopathy
APP is cleaved by proteases called secretases[@selkoe1999]:
Amyloidogenic pathway (Aβ-producing):
- Beta-secretase (BACE1) cleavage at position 1 → sAPPβ + C99
- Gamma-secretase cleavage of C99 → Aβ peptides (Aβ40, Aβ42)
Non-amyloidogenic pathway (protective):
- Alpha-secretase cleavage at position 17 → sAPPα + C83
- Gamma-secretase cleavage of C83 → p3 peptide
Aβ peptides are toxic through multiple mechanisms[@haass2007]:
- Synaptic dysfunction: Impairs LTP, enhances LTD
- Oxidative stress: ROS generation
- Mitochondrial dysfunction: Energy failure
- Neuroinflammation: Microglial activation
- Tau pathology: Promotes tau hyperphosphorylation
- Calcium dysregulation: Homeostatic disruption
Targeting APP processing is a major therapeutic strategy[@haass2007]:
| Target |
Approach |
Status |
| BACE1 inhibitors |
Block beta-secretase |
Halted (toxicity) |
| Gamma-secretase inhibitors |
Block Aβ production |
Halted (side effects) |
| Modulators |
Alter cleavage specificity |
Research |
| Alpha-secretase activators |
Enhance non-amyloidogenic pathway |
Research |
- Aducanumab (Aduhelm): Anti-Aβ antibody approved for AD
- Lecanemab (Leqembi): Anti-Aβ protofibril antibody
- Donanemab: Anti-Aβ plaque antibody
- Active vaccination approaches
- Silencing APP expression
- Delivering secretase modulators
- Bypassing mutant APP
- Goldgaber D, et al., Characterization and chromosomal localization of a cDNA encoding amyloid precursor protein in Alzheimer's disease (1987)
- Selkoe DJ, et al., Cell biology of the beta-amyloid precursor protein and the genetics of Alzheimer's disease (1999)
- Walsh DM, et al., The physiology and pathology of the amyloid precursor protein (2005)
- Haass C, et al., The amyloid beta peptide and Alzheimer disease (2007)
- Goedert M, et al., APP and Alzheimer's disease (2006)
- Hardy J, et al., Amyloid, APP and the genetics of Alzheimer's disease (2000)
- Bertram L, et al., The genetics of Alzheimer's disease (2008)
- Salloway S, et al., Amyloid-directed immunotherapy for Alzheimer's disease (2009)
- Karran E, et al., The amyloid cascade hypothesis: progress and prospects (2011)
- Mullan M, et al., A familial Alzheimer's disease mutation on the amyloid precursor protein gene (1992)