Characterization of Neuroprotective Reactive Astrocytes in the Aging Mammalian Brain

Abstract

The brain manifests cognitive deficits in aging and becomes more vulnerable to neurodegeneration. Astrocytes play several critical roles in the brain, including synapse formation, maturation, elimination, and synaptic plasticity, and impairments in these functions have more tremendous implications for diseases and neuronal dysfunction. Astrocytes sense and respond to different pathological stimuli through a process termed astrocyte reactivity, in which astrocytes undergo molecular, cellular, and functional changes. Generally, reactive astrocytes are considered to be a beneficial partner of neurons in the CNS. However, they can adopt a detrimental state as well, depending on the nature of the stimuli. Recent studies reported that astrocytes take on an LPS-induced neuroinflammatory phenotype during aging, which may facilitate synapse elimination and predispose the brain to neurodegeneration. Our lab recently showed that astrocyte-specific deletion of the stimulus-dependent transcription factor, SRF (SrfGFAPCKO and SrfGFAP−ERCKO) resulted in reactive astrocytes, which supports normal cell counts and brain architecture, normal synapse numbers, synaptic plasticity, and spatial memory and also induced microgliosis. Interestingly, SrfGFAP−ERCKO mice confer a significant level of neuroprotection to hippocampal neurons following kainate-induced excitotoxicity and dopaminergic neuron of substantia nigra following 6-hydroxydopamine administration. In a mouse model of Alzheimer’s disease, the SRF-deficient reactive astrocytes caused a significant reduction of β-amyloid plaques in the neocortex and hippocampus. Considering the neuroprotective nature of SRF-deficient reactive astrocytes, we hypothesized that “SRF-deficient reactive astrocytes can alleviate aging-associated changes in the brain.” Here, using RNA seq profiling and different staining methods, we show that SRF deficient reactive astrocytes persisted lifelong and adopted neuroprotective phenotype during aging, which is shown by significantly protected cerebellar Purkinje neurons, and synapse number from age-associated loss, and reduced myelin loss in the hippocampal regions. Microgliosis induced by SRF-deficient reactive astrocytes also lasts throughout life. Aged SrfGFAP−ERCKO mice brains have a significantly increased number of Olig2+ cells. KEGG pathway analysis, GO analysis for biological process and gene expression analysis helped us to examine the broad range of transcriptional changes happening in aged SRF-deficient reactive astrocytes. These analyses have shown that pathways related to functions of neurons, synapses, and behavior are upregulated, whereas highlighted downregulated pathways are aging, AD, HD, and PD. We have also shown that aged SrfGFAP−ERCKO exhibited better motor coordination and balance. Together these findings demonstrate that SRF-deficient reactive astrocytes can ameliorate aging-associated changes.