TY - JOUR
T1 - Mutant ubiquitin decreases amyloid beta plaque formation in a transgenic mouse model of Alzheimer's disease
AU - van Tijn, Paula
AU - Dennissen, Frank J. A.
AU - Gentier, Romina J. G.
AU - Hobo, Barbara
AU - Hermes, Denise
AU - Steinbusch, Harry W. M.
AU - Van Leeuwen, Fred W.
AU - Fischer, David F.
PY - 2012/10
Y1 - 2012/10
N2 - 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 beta (A beta) 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 A beta levels at 3, 6, 9 and 11 months of age. Surprisingly, we found a significant decrease in A beta deposition in amyloid plaques and levels of soluble A beta(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 A beta 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 A beta reduction. The molecular mechanism underlying this decrease in A beta 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).
AB - 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 beta (A beta) 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 A beta levels at 3, 6, 9 and 11 months of age. Surprisingly, we found a significant decrease in A beta deposition in amyloid plaques and levels of soluble A beta(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 A beta 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 A beta reduction. The molecular mechanism underlying this decrease in A beta 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).
KW - Alzheimer's disease
KW - Amyloid beta
KW - UBB+1
KW - Ubiquitin-proteasome system
U2 - 10.1016/j.neuint.2012.07.007
DO - 10.1016/j.neuint.2012.07.007
M3 - Article
C2 - 22797007
SN - 0197-0186
VL - 61
SP - 739
EP - 748
JO - Neurochemistry International
JF - Neurochemistry International
IS - 5
ER -