Abeta inhibits the proteasome and enhances amyloid and tau accumulation.
The accumulation of misfolded protein aggregates is a common feature of numerous neurodegenerative disorders including Alzheimer disease (AD). Here, we examined the effects of different assembly states of amyloid beta (Abeta) on proteasome function. We find that Abeta oligomers, but not monomers, inhibit the proteasome in vitro. In young 3xTg-AD mice, we observed impaired proteasome activity that correlates with the detection of intraneuronal Abeta oligomers. Blocking proteasome function in pre-pathological 3xTg-AD mice with specific inhibitors causes a marked increase in Abeta and tau accumulation, highlighting the adverse consequences of impaired proteasome activity for AD. Lastly, we show that Abeta immunotherapy in the 3xTg-AD mice reduces Abeta oligomers and reverses the deficits in proteasome activity. Taken together, our results indicate that Abeta oligomers impair proteasome activity, contributing to the age-related pathological accumulation of Abeta and tau. These findings provide further evidence that the proteasome represents a viable target for therapeutic intervention in AD.
Tseng
Bertrand P
BP
Department of Neurobiology and Behavior, University of California, 1109 Gillespie Neuroscience Research Facility, Irvine, CA 92697-4545, USA.
Green
Kim N
KN
Chan
Julie L
JL
Blurton-Jones
Mathew
M
LaFerla
Frank M
FM
D000375:Aging / Q000378:metabolism*; D000682:Amyloid / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism*; D002474:Cell-Free System; D005260:Female; D008297:Male; D051379:Mice; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D016875:tau Proteins / Q000378:metabolism*
D000682:Amyloid; D016229:Amyloid beta-Peptides; D016875:tau Proteins; D046988:Proteasome Endopeptidase Complex