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Acyl‐CoA synthetase 6 is required for brain docosahexaenoic acid retention and neuroprotection during aging

The omega‐3 fatty acid docosahexaenoic acid (DHA) inversely relates to neurological impairments with aging. However, limited non‐dietary in vivo models specifically depleting brain DHA have limited direct linkage of DHA to neurological aging processes. We discovered that loss of long‐chain acyl‐CoA synthetase 6 (ACSL6) depletes brain membrane phospholipid DHA levels. Here, the effects of membrane phospholipid DHA depletion on behavioral and neurological outcomes across the natural progression of aging in control and Acsl6 knockout mice (Acsl6‐/‐) were determined. Across the lifespan, Acsl6‐/‐ brains contained lower DHA compared to controls. The loss of DHA‐enriched and increased arachidonic acid‐enriched phospholipids was visualized by MALDI imaging, predominantly in neuronal rich regions where robust Acsl6 gene expression localized by smFISH to neurons across the brain, including pyramidal, Purkinje, and within the cerebellar granular layer. ACSL6 was also found in astrocytes; however, astrocyte‐specific loss of ACSL6 did not regulate membrane DHA, a phenomenon attributed to astrocyte‐specific expression of alternative‐exon ACSL6 variants that do not prefer DHA as substrate. Total ACSL6 knockout mice exhibited hyperlocomotion across the lifespan, early‐onset impairments in working spatial memory, and increased expression of cholesterol biosynthesis genes. In response to aging, cerebellar neuroinflammation and gliosis developed. Neuroinflammation was not accompanied by major alterations of lipid mediators but was preceded by decreased expression of synaptic proteins. Together our findings suggest that ACSL6 is enriched in neurons to promote membrane DHA enrichment, is important for brain DHA levels across the lifespan, protects against disordered motor function, memory, and age‐related neuroinflammation reflecting the importance of DHA, and its metabolism by ACSL6, early in life and in age‐related neuroprotection.