Impaired 26S proteasome causes learning and memory deficiency and induces neuroinflammation mediated by NF-κB in mice

Abstract

Aging and many neurodegenerative disorders, including Alzheimer disease (AD), show reduced proteasome activity, loss of synapses and increased neuroinflammation in the brain. However, whether proteasome dysfunction causes neuroinflammation remains less understood. Here, we studied the effect of impaired 26S proteasome on neuroinflammation in the Psmc1 knockout (KO) mice deficient of a 19S proteasome subunit selectively in the forebrain region. We initially assessed the proteasome activity in the KO and control mouse brains and performed cognitive behavioral test to the animals. The synaptosomes were isolated from the forebrain and subjected to mass spectrometric analysis of total synaptic proteins. The identified synaptic proteins were then assessed using bioinformatic approaches. To validate identified proteins, Western blot analysis and immunofluorescent staining of specific protein were utilized. To validate NF-kB mediating neuroinflammation, we administered the KO animals at 5 weeks of age with a selective NF-kB inhibitor for three weeks and then, animal behaviors and neuroinflammation were assessed when they reached to eight weeks of age. Our results revealed that impaired 26S proteasome led to AD-like cognitive deficiency and overt neuroinflammation in the synapses of the Psmc1 KO brain at eight weeks of age. Pronounced neuroinflammation also occurred in other regions and glial cells, which was confirmed by increased levels of several key immune response-related proteins, including Stat1, Trem2 and NF-kB, and by activation of astrocytes and microglia in the KO brain. Following treating the KO mice with a selective NF-kB inhibitor, the KO mice exhibited improved behaviors and reduced neuroinflammation compared to the control animals. These data indicate that impaired 26S proteasome causes AD-like cognitive deficiency and induces neuroinflammation mediated largely by NF-kB, which will help develop effective therapeutics and aid to better understand the pathogenesis of AD and many other neurodegenerative disorders where impaired proteasome is consistently coupled with neuroinflammation.