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. Overall design: 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.

阐明与年龄相关的认知衰退的细胞与分子驱动机制，是识别老年阶段认知功能修复靶点的必要前提。本研究发现铁蛋白轻链1（ferritin light chain 1, FTL1）是一种促衰老神经元因子，可损伤认知功能。在老年小鼠海马体中靶向干预神经元FTL1，可诱发突触相关及代谢相关的分子改变，并逆转认知损伤。本研究数据证实，神经元FTL1是认知年轻化的关键分子介质。

整体实验设计如下：
为模拟年龄相关性神经元FTL1水平升高并评估其效应，我们对年轻小鼠海马体实施双侧立体定位注射，将高滴度慢病毒注入其海马体，该病毒携带受神经元特异性Syanpsin-1启动子调控的Ftl1或GFP（作为对照）。随后，我们通过对过表达Ftl1或GFP（对照组）的年轻小鼠的神经元细胞核进行RNA测序，获取数据并开展表达谱分析。
为探究靶向干预年龄相关性海马体FTL1升高的潜在益处，我们对老年小鼠海马体实施双侧立体定位注射，将高滴度慢病毒注入其海马体，该病毒编码靶向Ftl1的shRNA序列，或靶向荧光素酶的阴性对照shRNA序列。随后，我们通过对对照组及Ftl1敲低（KD）老年小鼠的神经元细胞核进行RNA测序，获取数据并开展表达谱分析。
为探究海马体神经元在衰老过程中发生的分子改变，我们通过荧光激活细胞分选（fluorescence activated cell sorting, FACS）技术，从年轻（3月龄）及老年（18月龄）野生型（wild type, wt）小鼠的海马体中分离出NeuN阳性神经元细胞核。随后，我们对年轻及老年野生型小鼠的神经元细胞核进行RNA测序，获取数据并开展表达谱分析。