Asrij/OCIAD1 contributes to age-associated microglial activation and neuroinflammation in mice

Prathamesh Dongre¹Madhu Ramesh¹Thimmaiah Govindaraju^1*Maneesha S. Inamdar^1,2*

• ¹Jawaharlal Nehru Centre for Advanced Scientific Research, Bengaluru, India
• ²Institute for Stem Cell Science and Regenerative Medicine, Bengaluru, India

Aging is characterized by chronic low-grade neuroinflammation that increases the risk of neurodegenerative disorders. Neuroinflammation, driven by activation of astrocytes and microglia, underlies age-associated cognitive deficits. Amplified neuroinflammatory responses upon immune challenge are attributed to microglial activation in the aged brain. Despite extensive clinical and experimental evidence linking neuroinflammation to aging, the molecular players that control the age-associated neuroinflammatory response of the brain are not fully understood. Genome-wide associated studies (GWAS) and proteomics and transcriptomic datasets revealed Asrij/OCIAD1 as a novel aging and Alzheimer's disease (AD) associated factor. Asrij levels are increased in AD patients and known to promote amyloid-beta (Ab) pathology and microglia-mediated neuroinflammation, associated with cognitive dysfunction in AD. Increased levels of Asrij are also reported in the brains of aged wild-type (WT) mice, however whether this may promote neuroinflammation or be a protective response during aging, is not known. To test this, we used the young and aged WT and asrij KO mice and show that normal aging is associated with increased microgliosis and astrocyte activation in WT mice. While young asrij KO mice do not display any differences in glial activation, aged KO mice have reduced microglial and astrocytic activation compared to aged WT mice. This is accompanied by reduced levels of pro-inflammatory mediators and downregulation of STAT3 and NF-kB signaling in the cortex and hippocampus of aged asrij KO mice. Additionally, asrij depletion inhibited LPS-induced microglial activation and neuroinflammation in the aged mice. This indicates that Asrij is essential for neuroinflammatory responses in the aged mouse brain. We propose that identifying pharmaceutical modulators of Asrij could provide novel means to control microglial activation and neuroinflammation during normal aging.