Alzheimer’s disease is another disorder marked by the inappropriate activity of matrix metalloproteases. A major pathological change associated with Alzheimer’s disease is accumulation in the brain of amyloid plaques containing aggregates of a small 42-amino-acid peptide termed Aβ₄₂. This peptide is derived by proteolytic cleavage of amyloid precursor protein (APP), a transmembrane cell-surface protein of still mysterious function expressed by neurons.

Like Notch protein, APP undergoes one extracellular cleavage and one intramembrane cleavage (Figure 16-37a), but this can happen in two ways. In the first, APP is cleaved at a site in the extracellular domain by ADAM 10 (often called α-secretase), and then by γ-secretase at a single intramembrane site, releasing the APP cytosolic domain and generating a 26-amino-acid, partially membrane-embedded peptide that apparently does no harm. In contrast, if the extracellular domain is first cleaved at a different site by a different enzyme, β-secretase, and then by γ-secretase at the same intermembrane site, a 42-amino-acid peptide, termed Aβ₄₂, is generated. Aβ₄₂ spontaneously forms oligomers and then the larger amyloid plaques found in the brain of patients with Alzheimer’s disease.

APP was recognized as a major player in Alzheimer’s disease through a genetic analysis of the small percentage of patients with a family history of the disease. Many had mutations in the APP protein, and intriguingly, these mutations are clustered around the cleavage sites of α-, β-, or γ-secretase depicted in Figure 16-37a. Other cases of familial Alzheimer’s disease involve missense mutations in presenilin 1, the catalytic subunit of γ-secretase, that enhance the formation of the Aβ₄₂ peptide, leading to plaque formation and eventually to the death of neurons.