APP and Alzheimer disease: Dr. Emil Kraepelin termed this triad of features “Alzheimer’s disease.” SPs found in the extracellular matrix consist of insoluble fibrils of Aβ, produced from a larger transmembrane amyloid-β precursor protein (APP) by the successive cleavage by the β-site APP cleaving enzyme 1 (BACE1) and the intramembrane γ-secretase complex (Shoji et al., 1992; Thinakaran and Koo, 2008).