Mutant ubiquitin decreases amyloid β plaque formation in a transgenic mouse model of Alzheimer’s disease

► UBB+1 modulates Aβ aggregation during the critical period of plaque formation. ► UBB+1 is ubiquitinated at K63 allowing nonsubstrate linked polyubiquitin chains. ► UBB+1 capped unanchored polyubiquitin chains may regulate the NF-κB pathway. The mutant ubiquitin UBB+1 is a substrate as well as an inhibitor of the ubiquitin–proteasome system (UPS) and accumulates in the neuropathological hallmarks of Alzheimer’s disease (AD). A role for the UPS has been suggested in the generation of amyloid β (Aβ) plaques in AD. To investigate the effect of UBB+1 expression on amyloid pathology in vivo, we crossed UBB+1 transgenic mice with a transgenic line expressing AD-associated mutant amyloid precursor protein (APPSwe) and mutant presenilin 1 (PS1dE9), resulting in APPPS1/UBB+1 triple transgenic mice. In these mice, we determined the Aβ levels at 3, 6, 9 and 11months of age. Surprisingly, we found a significant decrease in Aβ deposition in amyloid plaques and levels of soluble Aβ42 in APPPS1/UBB+1 transgenic mice compared to APPPS1 mice at 6months of age, without alterations in UBB+1 protein levels or proteasomal chymotrypsin activity. These lowering effects of UBB+1 on Aβ deposition were transient, as this relative decrease in plaque load was not significant in APPPS1/UBB+1 mice at 9 and 11months of age. We also show that APPPS1/UBB+1 mice exhibit astrogliosis, indicating that they may not be improved functionally compared to APPPS1 mice despite the Aβ reduction. The molecular mechanism underlying this decrease in Aβ deposition in APPPS1/UBB+1 mice is more complex than previously assumed because UBB+1 is also ubiquitinated at K63 opening the possibility of additional effects of UBB+1 (e.g. kinase activation).