Abstract
BackgroundOlder-age individuals are at the highest risk for disability from a traumatic brain injury (TBI). Astrocytes are the most numerous glia in the brain, necessary for brain function, yet there is little known about unique responses of astrocytes in the aged-brain following TBI.MethodsOur approach examined astrocytes in young adult, 4-month-old, versus aged, 18-month-old mice, at 1, 3, and 7 days post-TBI. We selected these time points to span the critical period in the transition from acute injury to presumably irreversible tissue damage and disability. Two approaches were used to define the astrocyte contribution to TBI by age interaction: (1) tissue histology and morphological phenotyping, and (2) transcriptomics on enriched astrocytes from the injured brain.ResultsAging was found to have a profound effect on the TBI-induced loss of astrocyte function needed for maintaining water transport and edema—namely, aquaporin-4. The aged brain also demonstrated a progressive exacerbation of astrogliosis as a function of time after injury. Moreover, clasmatodendrosis, an underrecognized astrogliopathy, was found to be significantly increased in the aged brain, but not in the young brain. As a function of TBI, we observed a transitory refraction in the number of these astrocytes, which rebounded by 7 days post-injury in the aged brain. Transcriptomic data demonstrated disproportionate changes in genes attributed to reactive astrocytes, inflammatory response, complement pathway, and synaptic support in aged mice following TBI compared to young mice. Additionally, our data highlight that TBI did not evoke a clear alignment with the previously defined “A1/A2” dichotomy of reactive astrogliosis.ConclusionsOverall, our findings point toward a progressive phenotype of aged astrocytes following TBI that we hypothesize to be maladaptive, shedding new insights into potentially modifiable astrocyte-specific mechanisms that may underlie increased fragility of the aged brain to trauma.
Highlights
Older-age individuals are at the highest risk for disability from a traumatic brain injury (TBI)
TBI elicits delayed reactive gliosis that is protracted in the aged brain To examine whether reactive astrogliosis is sensitive to age at the time of injury, as well as the progression of time after injury, we examined Glial fibrillary acid protein (GFAP) reactivity in the ipsilateral dorsal hippocampal formation and adjacent neocortex
We found a TBI-induced increase in both hippocampal and cortical GFAP+ astrogliosis over the first 7 days post-injury in both young and aged animals (Fig. 1)
Summary
Older-age individuals are at the highest risk for disability from a traumatic brain injury (TBI). As a variety of roles of astrocytes within the disease or injury milieu are being identified, it is becoming clearer that astrocyte response is rather heterogeneous [17, 20, 22,23,24], with implications pointing toward a diversity of graded responses [25] Among these responses are multiple domains encompassing inflammatory response, tissue protection, vascular response, as well as neuronal functionality [26]. Aged astrocytes were shown to disproportionately respond to an inflammatory challenge (e.g., LPS), compared to young [28] These works proposed that the aged brain promotes a “neurotoxic” bias in astrocytes predominated by a pro-inflammatory response, with permissive phenotypes supporting increased synaptic clearance and neuronal damage [28, 29]. In this study we aimed to define astrocyte-specific morphological and transcriptional phenotypes using wellcharacterized homeostatic and disease-associated substrates
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