A reduction in proteasome activity, loss of synapses, and increased neuroinflammation in the brain are hallmarks of aging and many neurodegenerative disorders, including Alzheimers 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 causes reduced learning and memory capability and overt neuroinflammation in the Psmc1 KO brain at eight weeks of age. Pronounced neuroinflammation was confirmed by increased levels of several key immune response-related proteins, including Stat1, Trem2, and NF-{kappa}B, and by activation of astrocytes and microglia in the KO brain. To validate NF-{kappa}B mediating neuroinflammation, we administered a selective NF-{kappa}B inhibitor to the KO animals, and following the treatment, the KO mice exhibited improved learning and memory 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-{kappa}B. These results may aid the development of effective therapeutics for AD and other neurodegenerative disorders where impaired proteasome activity is consistently coupled with neuroinflammation.
Longevity Relevance Analysis
(3)
The paper investigates the role of impaired 26S proteasome activity in neuroinflammation and cognitive decline, which are associated with aging and neurodegenerative diseases like Alzheimer's. While it addresses a mechanism that could contribute to age-related cognitive decline, the focus is primarily on the symptoms and consequences of proteasome dysfunction rather than directly targeting the root causes of aging. The findings may contribute to understanding neuroinflammation in the context of aging, but the impact on longevity research is limited, hence the score of 3.