PT  - JOURNAL ARTICLE
AU  - Alexandria N. Early
AU  - Amy A. Gorman
AU  - Linda J. Van Eldik
AU  - Adam D. Bachstetter
AU  - Josh M. Morganti
TI  - Effects of advanced age upon astrocyte-specific responses to acute traumatic brain injury in mice
AID  - 10.1101/845883
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 845883
4099  - http://biorxiv.org/content/early/2019/11/17/845883.short
4100  - http://biorxiv.org/content/early/2019/11/17/845883.full
AB  - Background Older-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.Methods Our 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.Results Aging was found to have a profound effect on the TBI-induced loss of homeostatic astrocyte function needed for maintaining water transport and edema – namely, aquaporin-4. The loss of homoeostatic responses was coupled with a progressive exacerbation of astrogliosis in the aged brain 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. The transcriptomics found 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 previously defined “A1/A2” dichotomy of reactive astrogliosis.Conclusions Overall, 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.AbbreviationsADAlzheimer’s diseaseAqp4Aquaporin4ACSA-2Astrocyte Cell Surface Antigen 2BBBBlood brain barrierCBFCerebral blood flowCSFCerebral spinal fluidCTEChronic Traumatic EncephalopathyCCIControlled cortical impactCA1Cornu Ammonis area 1DAMPsDamage-associated molecular patternsGFAPGlial fibrillary acid proteinHPCHippocampusLPSLipopolysaccharideMCAOMiddle cerebral artery occlusionNGSNormal goat serumPFAParaformaldehydePBSPhosphate buffered salinePCAPrincipal Component AnalysisSCISpinal cord injuryTLDATaqman low density arrayTBITraumatic brain injury