APP Processing and Plaque Formation

Alzheimer's disease (AD), the most prevalent neurodegenerative disorder in aged population, is characterized by progressive cognitive impairment and other neurodegeneration disorder. Neuropathological hallmarks of AD include neuronal loss in the neurofibrillary tangles (NFTs) and presence of extracellular neuritic plaques in the brain. The NFTs is formed of hyperphosphorylated twisted filaments of the microtubule-associated protein Tau. While, extracellular neuritic plaques are deposits of differently sized small peptides called beta-amyloid (Aβ), which are derived via sequential proteolytic cleavages of the beta-amyloid precursor protein (APP).


APP belongs to a larger evolutionarily conserved APP superfamily protein family that includes the APP itself and amyloid precursor-like protein 1 (APLP1) and 2 (APLP2) in mammals. The APP superfamily shares several conserved domains, however, only APP generates an amyloidogenic fragment owing to the unique Aβ domain in sequence divergence. Though expressed in many tissues, APP is concentrated in the synapses of neurons in the CNS. All of them are single-pass transmembrane proteins with large extracellular N terminal and a shorter cytoplasmic C terminal.

Diagram of APP structure

Figure 1. Diagram of APP structure.

APP processing

APP can be sequentially cleaved in two different ways by different sets of enzymes: an amyloidogenic pathway leads to amyloid plaque formation (Fig. 2, right), while a canonical pathway does not (non-amyloidogenic) (Fig. 2, left). In general, almost 90% of APP undergoes the non-amyloidogenic canonical pathway, and 10% the amyloidogenic pathway. However, the ratio can be altered by genetic mutations, environmental factors and the age of the individual. Cleavage products of APP from both pathways play diverse roles that are important in neural development and function.

APP processing

Figure 2. APP processing: enzymes and cleavage products. (Fraering PC, 2007)

The Canonical Pathway

Canonical processing of APP is catalyzed by α-secretase, resulting in the generation of two fragments: a large extracellular fragment secreted APP (sAPP) α (sAPPα) that is released to extracellular medium, as well as an83 amino acid C-terminal fragment α-carboxyterminal fragments (CTF) that remains in the membrane. The cleavage site of APP by α-secretase lies within the Aβ sequence and thus prohibits Aβ peptide production. α-Secretase activity is mediated by one or more enzymes from the family of disintegrin and metalloproteinase domain proteins (ADAM), of which three enzymes have been identified: ADAM9, ADAM10, and ADAM17. α-CTF is subsequently cleaved by γ-secretase, producing a short fragment called P3 peptide and the amino-terminal APP intracellular domain (AICD). γ-secretase is a complex of enzymes consisting of presenilin 1 or 2 (PS1 and PS2), nicastrin, anterior pharynx defective (APH-1) and presenilin enhancer 2 (PEN2).

The Amyloidogenic Pathway

The amyloidogenic pathway occurs as APP interacts with β-secretase in the endocytic pathway. β-secretase (BACE1, the major β-secretase in the brain) mediates the first proteolysis step in mature endosomes, releasing a large N-terminal ectodomain sAPPβ into the extracellular medium and a longer C-terminal fragment β-CTF with 99-amino acids remaining in the membrane. The β-CTF fragment is cleaved by γ-secretase. The successive cleavage of CTFβ leads to the generation of AICD, as well as Aβ peptides being secreted outside the cell. Most of the Aβ peptides are 40 residues in length (Aβ 1-40), with a small percentage containing 42 residues (Aβ 1-42). Increased extracellular accumulation of toxic Aβ species, particularly Aβ 1-42, will further lead to the formation of Aβ oligomers. Monomeric and oligomeric forms of Aβ overwhelm the brains capacity for clearance and degradation and form extracellular plaques, causing neurotoxicity through several mechanisms including microglial infiltration, oxidative stress, and synaptic damage.


1. Zhang Y, Thompson R, Zhang H, et al. APP processing in Alzheimer's disease. Molecular brain, 2011, 4(1): 3.
2. O'Brien R J, Wong P C. Amyloid precursor protein processing and Alzheimer's disease. Annual review of neuroscience, 2011, 34: 185-204.
3. Wilquet V, De Strooper B. Amyloid-beta precursor protein processing in neurodegeneration. Current opinion in neurobiology, 2004, 14(5): 582-588.

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