Figure 1

Pathogenesis of Alzheimer's disease: potential roles of the ubiquitin proteasome system. The figure summarizes the two major hypotheses (Aβ and tau) of AD pathology and the linkage of UPS to AD pathogenesis. Extracellular amyloid plaques consisting of insoluble Aβ peptide and intracellular neurofibrillary tangles comprising hyperphosphorylated protein tau are the two major features evident in the post mortem AD brain. Although the figure depicts only increased production of Aβ₄₂ (a splice variant of Aβ, some familial Alzheimer's disease (FAD) mutations in APP or PSEN 1 also lead to increased Aβ₄₂ secretion [71]. The roles of the UPS in the steps leading to AD pathogenesis are shown in green boxes. The ubiquitin mutant UBB⁺¹ is also linked to AD, though it is unclear at present how pathogenesis mediated by UBB⁺¹ relates to the major AD hypotheses. Abbreviations used are: Aβ, amyloid β; AD, Alzheimer's disease; APP, amyloid precursor protein; MAP, microtubule associated protein; PHFs, paired helical filaments; Ub, ubiquitin; UPS, ubiquitin proteasome system.