Functional and transcriptional profiling of microglial activation during the chronic phase of TBI identifies an age-related driver of poor outcome in old mice.
Rodney M RitzelYun LiZhuofan LeiJordan CarterJunyun HeHarry M C ChoiNiaz KhanHui LiSamantha AllenMarta M LipinskiAlan I FadenJunfang WuPublished in: GeroScience (2022)
Elderly patients with traumatic brain injury (TBI) have greater mortality and poorer outcomes than younger individuals. The extent to which old age alters long-term recovery and chronic microglial activation after TBI is unknown, and evidence for therapeutic efficacy in aged mice is sorely lacking. The present study sought to identify potential inflammatory mechanisms underlying age-related outcomes late after TBI. Controlled cortical impact was used to induce moderate TBI in young and old male C57BL/6 mice. At 12 weeks post-injury, aged mice exhibited higher mortality, poorer functional outcomes, larger lesion volumes, and increased microglial activation. Transcriptomic analysis identified age- and TBI-specific gene changes consistent with a disease-associated microglial signature in the chronically injured brain, including those involved with complement, phagocytosis, and autophagy pathways. Dysregulation of phagocytic and autophagic function in microglia was accompanied by increased neuroinflammation in old mice. As proof-of-principle that these pathways have functional importance, we administered an autophagic enhancer, trehalose, in drinking water continuously for 8 weeks after TBI. Old mice treated with trehalose showed enhanced functional recovery and reduced microglial activation late after TBI compared to the sucrose control group. Our data indicate that microglia undergo chronic changes in autophagic regulation with both normal aging and TBI that are associated with poorer functional outcome. Enhancing autophagy may therefore be a promising clinical therapeutic strategy for TBI, especially in older patients.
Keyphrases
- traumatic brain injury
- severe traumatic brain injury
- inflammatory response
- cell death
- high fat diet induced
- mild traumatic brain injury
- drinking water
- neuropathic pain
- lipopolysaccharide induced
- lps induced
- oxidative stress
- gene expression
- cardiovascular disease
- adipose tissue
- cardiovascular events
- risk assessment
- high intensity
- type diabetes
- genome wide
- health risk assessment
- dna methylation
- metabolic syndrome
- human health
- brain injury
- gestational age
- blood brain barrier
- big data
- electronic health record
- skeletal muscle
- copy number
- resting state
- cognitive impairment
- binding protein
- single cell
- white matter
- functional connectivity