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

A reduction in proteasome activity, loss of synapses and increased neuroinflammation in the brain are hallmarks of aging and many neurodegenerative disorders, including Alzheimer disease (AD); however, whether proteasome dysfunction is causative to neuroinflammation remains less understood. In this study, we investigated the impact of 26S proteasome deficiency on neuroinflammation in the Psmc1 knockout (KO) mice deficient in a 19S proteasome subunit limited to the forebrain region. Our results revealed that impaired 26S proteasome led to reduced learning and memory capability and overt neuroinflammation in the synapses of the Psmc1 KO brain at eight weeks of age. Moreover, pronounced neuroinflammation was also found in the whole brain cortex, which was confirmed by increased levels of several key immune response-related proteins, including Stat1, Trem2 and NF-κB, and by activation of astrocytes and microglia in the KO brain. To validate NF-κB mediating neuroinflammation, we administered a selective NF-κB inhibitor to the KO animals at 5 weeks of age for three weeks, and then, animal behaviors and neuroinflammation were assessed when they reached eight weeks of age. Following the treatment, 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-κB. These results may aid development of effective therapeutics and better understanding of the pathogenesis of AD and many other neurodegenerative disorders where impaired proteasome is consistently coupled with neuroinflammation.