Nipsnap 1 deficiency shifts neuronal and synaptic signaling toward inflammatory pathway and impairs cognitive functions in the aging brain

Abstract

Mitochondrial quality control is essential for maintaining neuronal function during aging. Nipsnap1 (Nip1), a mitochondrial protein involved in mitophagy, metabolic regulation, and cellular senescence, has emerged as a potential regulator of tissue homeostasis; however, its role in brain aging remains unclear. Here, we investigated the consequences of constitutive Nip1 deficiency using transcriptomic, histological, biochemical, behavioral, and metabolomic approaches in aged mice. Bulk RNA sequencing of cortical and hippocampal tissues from 15-month-old Nip1 knockdown (Nip1KD) mice revealed widespread transcriptional alterations, including downregulation of neuronal and synaptic pathways and upregulation of neuroinflammatory and innate immune programs. Disease-associated microglial genes, including Trem2, Apoe , and C1q family members, were significantly elevated. Histological analyses demonstrated reduced neuronal density, increased microglial activation, and enhanced apoptosis. Functional analyses of isolated brain mitochondria showed elevated reactive oxygen species production, reduced NAD⁺/NADH ratios, and altered bioenergetic status, consistent with mitochondrial dysfunction and redox imbalance. Behavioral assessments revealed impairments in spatial working and recognition memory. Metabolomic profiling identified broad disruptions in nucleotide, lipid, amino acid, and redox metabolism. Several pathological and behavioral phenotypes were more pronounced in females. Collectively, these findings identify Nip1 as a critical regulator of mitochondrial homeostasis, neuroimmune balance, and neuronal integrity during brain aging.