MAPT and Alzheimer disease: Therefore, the following should be taken into consideration: (1) Elevation of ubiquitin several folds in the AD brain and ubiquitin-positive inclusions being common in neurodegeneration; (2) the spatiotemporal order of tau phosphorylation, oligomerization, and ubiquitination during the formation of PHF; (3) loss of proteasome activity in the AD brain (56); and (4) the neurotoxicity of oligomer tau rather than PHF (57, 58).