APP (Amyloid Precursor Protein) is a transmembrane glycoprotein that is central to the pathogenesis of [Alzheimer's disease](/diseases/alzheimers-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.
Gene Information
Protein Structure
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.
Biological Functions
Synaptic Function
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
Protein Trafficking
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
Neuroprotection
APP has neuroprotective properties:
Contains a growth factor-like domain
May protect against oxidative stress
Supports neuronal survival during development
May have trophic functions
Expression Pattern
Brain Expression
APP is expressed throughout the brain[@walsh2005]:
Subcellular Localization
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
Role in Alzheimer's Disease
Genetic Evidence
APP mutations cause familial Alzheimer's disease[@goldgaber1987]:
Swedish mutation (KM670/671NL): Double mutation increasing Aβ production
London mutation (V717I): Alters gamma-secretase cleavage
[Tau Protein](/proteins/tau-protein) — Tau pathology
[Down Syndrome](/diseases/down-syndrome) — APP on chr 21
References
[Goldgaber D, et al., Characterization and chromosomal localization of a cDNA encoding amyloid precursor protein in Alzheimer's disease (1987)](https://pubmed.ncbi.nlm.nih.gov/3431208/)
[Selkoe DJ, et al., Cell biology of the beta-amyloid precursor protein and the genetics of Alzheimer's disease (1999)](https://pubmed.ncbi.nlm.nih.gov/10588743/)
[Walsh DM, et al., The physiology and pathology of the amyloid precursor protein (2005)](https://pubmed.ncbi.nlm.nih.gov/16023167/)
[Haass C, et al., The amyloid beta peptide and Alzheimer disease (2007)](https://pubmed.ncbi.nlm.nih.gov/17520608/)
[Goedert M, et al., APP and Alzheimer's disease (2006)](https://pubmed.ncbi.nlm.nih.gov/16777669/)
[Hardy J, et al., Amyloid, APP and the genetics of Alzheimer's disease (2000)](https://pubmed.ncbi.nlm.nih.gov/10830911/)
[Bertram L, et al., The genetics of Alzheimer's disease (2008)](https://pubmed.ncbi.nlm.nih.gov/18462017/)
[Salloway S, et al., Amyloid-directed immunotherapy for Alzheimer's disease (2009)](https://pubmed.ncbi.nlm.nih.gov/19668856/)
[Karran E, et al., The amyloid cascade hypothesis: progress and prospects (2011)](https://pubmed.ncbi.nlm.nih.gov/21844118/)
[Mullan M, et al., A familial Alzheimer's disease mutation on the amyloid precursor protein gene (1992)](https://pubmed.ncbi.nlm.nih.gov/1311757/)