The progression from proteolysis of the amyloid precursor protein (APP) to the formation of aggregated amyloid-β peptide (Aβ) deposits forms the basis of the amyloid hypothesis for the pathogenesis of Alzheimer disease.1 Key steps in APP processing occur in subcellular compartments. Amyloid-β is one of several end products that originate from the sequential proteolysis by β-secretase and γ-secretase cleavage of the transmembrane APP. While Aβ can range in size from 37 to 43 amino acids, it is the Aβ42 peptide that appears to be the foundation of fibrillar plaque formation in the brains of patients with Alzheimer disease. Alterations in the intracellular transport of APP can directly influence whether APP undergoes α-secretase enzymatic activity, releasing a nontoxic peptide, α-secretase–cleaved soluble APP (sAPPα), or follows β-secretase and γ-secretase enzymatic pathways, leading to generation of the neurotoxic forms of Aβ. While the α-secretase enzymes are found at the cell surface, β-secretase lies within the Golgi apparatus and endosomes, the γ-secretase complex in the endoplasmic reticulum, lysosomes, and the cell surface. When APP is moved into the endosome, it is cleaved by β-secretase and then transported either to the cell surface or to the lysosome to be further processed by γ-secretase to form Aβ. However, when APP accumulates at the cell surface, it has a greater chance of interacting with α-secretase to form nonamyloid-forming sAPPα.
Mayeux R, St. George-Hyslop P. Brain Traffic: Subcellular Transport of the Amyloid Precursor Protein. Arch Neurol. 2009;66(4):433–434. doi:10.1001/archneurol.2009.29
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