Mutant ubiquitin decreases amyloid β plaque formation in a transgenic mouse model of Alzheimer's disease.
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 11 months of age. Surprisingly, we found a significant decrease in Aβ deposition in amyloid plaques and levels of soluble Aβ(42) in APPPS1/UBB(+1) transgenic mice compared to APPPS1 mice at 6 months 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 11 months 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).
Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences, Meibergdreef 47, 1105 BA Amsterdam, The Netherlands.
Paula
P
van Tijn
Frank J A
FJ
Dennissen
Romina J G
RJ
Gentier
Barbara
B
Hobo
Denise
D
Hermes
Harry W M
HW
Steinbusch
Fred W
FW
Van Leeuwen
David F
DF
Fischer
D000544:Alzheimer Disease / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000235:genetics; D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D058225:Plaque, Amyloid / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D025801:Ubiquitin / Q000235:genetics* / Q000502:physiology
D016229:Amyloid beta-Peptides; C479419:UBB protein, human; D025801:Ubiquitin