APP processing and imbalance in age-related neurodegeneration. (a) The amyloid precursor protein is processed either by an amyloidogenic pathway (left) or a canonical pathway (right). Canonical processing by α-secretase results in secretion of a large extracellular fragment, sAPPα. Importantly, this cleavage occurs within the Aβ peptide fragment (light blue), preventing its formation. A membrane bound C-terminal fragment, CTFα, then becomes a substrate for γ-secretase. This cleavage occurs within the membrane, releasing a short extracellular p3 peptide, and the APP intracellular domain (AICD, dark blue). Amyloidogenic processing occurs as APP interacts with β-secretase, or BACE, in the endocytic pathway. This generates the secreted sAPPβ, and a longer C-terminal fragment, CTFβ; γ-secretase cleavage of this fragment generates Aβ and AICD. (b) In Down syndrome, the overexpression of APP on the cellular surface results in increased amounts of APP being endocytosed. In mature endosomes, BACE (an enzyme that is more active at acidic pH) then cleaves APP resulting in increased amounts of CTFβ and Aβ peptide (light blue) being secreted outside the cell. Increased extracellular accumulation of toxic Aβ species, particularly Aβ ₄₂, results in the formation of Aβ oligomers. These oligomers then overwhelm the brains capacity for clearance and degradation and form extracellular plaques, ultimately leading to neurodegeneration and severe brain atrophy. (c) Normally, most APP is cleaved by the α-secretase, secreting sAPPα. CTFα is endocytosed and then processed by γ-secretase, resulting in formation of the p3 peptide, which is secreted, and releasing the AICD into the cytosol. BACE processing of APP does occur to generate Aβ (blue), but these are degraded and cleared. While few small plaques may accumulate with aging, they are much smaller and fewer in number than those associated with disease.