Alzheimerʹs disease meets the ubiquitin–proteasome system

Ubiquitin-positive deposits are histopathologically found in patients with Alzheimerʹs disease (AD). It is not understood why ubiquitin is accumulated in intra- and extra-cellular deposits or how it is involved in AD pathogenesis. Interestingly, recent evidence, including studies of E2–25K/Hip-2, has elucidated the molecular mechanism of the ubiquitin–proteasome system (UPS) malfunction in AD. The neurotoxicity and proteasome inhibition by Aβ, a main cause of AD pathogenesis, are mediated by increased E2–25K/Hip-2 in the brains of patients with AD. Furthermore, E2–25K/Hip-2 is required for the neurotoxicity that is mediated by a ubiquitin B mutant (UBB+1), which is a potent inhibitor of proteasomes that is found in patients with AD. Intensive research is required to identify the components of the UPS that are involved in AD pathogenesis.