Targeting neuronal FTL1 rescues cognitive impairments in aging

Understanding cellular and molecular drivers of age-related cognitive decline is necessary to identify targets to restore cognition at old age. Here we report that ferritin light chain 1 (FTL1) is a pro-aging neuronal factor that impairs cognition. Targeting neuronal FTL1 in the hippocampi of aged mice elicits synaptic and metabolic-related molecular changes and rescues cognitive impairments. Our data identify neuronal FTL1 as a key molecular mediator of cognitive rejuvenation. To assess the effect of mimicking an age-related increase in neuronal FTL1, young mice were given bilateral stereotaxic injections of high titer lentivirus encoding Ftl1 or GFP under the control of the neuron-specific Syanpsin-1 promoter into their hippocampi. We then performed expression profiling analysis using data obtained from neuronal nuclei RNA-seq of young mice overexpressing Ftl1 or GFP (controls). To explore the potential benefit of targeting the age-related increase in hippocampal FTL1, aged mice were given bilateral stereotaxic injections of high-titer lentivirus encoding shRNA sequences targeting either Ftl1 or luciferase control into their hippocampus . We then performed expression profiling analysis using data obtained from neuronal nuclei RNA-seq of controls and Ftl1 KD aged mice. To assess the molecular changes in neurons that occur during aging in the hippocampus. NeuN-positive neuronal nuclei were isolated by fluorescence activated cell sorting (FACS) from hippocampi of young (3 months) and aged (18 months) wt mice. We then performed expression profiling analysis using data obtained from neuronal nuclei RNA-seq of young and old wt mice.