Proteolytic processes contribute to the amyloid cascade hypothesis. Aβ is generated from APP by concerted proteolysis by β-secretase, which generates carboxyl-terminal fragments (CTFs) of APP, and then by γ-secretase. The Aβ forms aggregates in the extracellular compartment as senile plaques through a process that depends on proteoglycans and apolipoproteins. The extracellular Aβ oligomers may activate caspases through activation of cell surface death receptors. Alternatively, intracellular Aβ may activate caspases through a process that involves ER stress or mitochondrial stress. One of the consequences of caspase activation is cleavage of tau, which favors conformational changes characteristic of paired helical filaments (PHF-tau). Progressive accumulation of tau leads to cytoskeletal disruption (inset), failure of axoplasmic and dendritic transport, and subsequent loss of trophic support that culminates in neuronal death. The extracellular amyloid deposits in senile plaques also trigger reactive glial changes and neuroinflammation that can also contribute to neuronal loss through production of reactive oxygen species (ROS), NO, and proinflammatory cytokines such as TNF-α and IL-1β. sAPPβ, secreted APPβ.