Mechanisms and Therapeutic Targeting of Chronic Neuroinflammation in Traumatic Brain Injury

Traumatic brain injury (TBI) is one of the leading causes of death and disability in the United States.
Research has shown that there is chronic neuroinflammation following TBI, which contributes to progressive
neurodegeneration, white matter loss and cognitive decline. Unfortunately, the pathological processes
underlying chronic neuroinflammation are poorly understood. The overall objective of the current study is to
elucidate the mechanisms that underlie chronic neuroinflammation after TBI and test therapeutic
interventions that target these mechanisms. Our central hypothesis is that newly discovered
proinflammatory and neurotoxic A1 astrocytes play a key role in chronic neuroinflammation, progressive
neurodegeneration, and cognitive decline long-term after TBI. A1 astrocytes are astrocytes that lose the
ability to carry out their normal functions, produce complement components, are less able to promote the
formation of new synapses, and release factors which can damage or kill neurons and oligodendrocytes [9].
Furthermore, our preliminary data indicates that A1 astrocytes express “senescent” markers and are
senescent, raising the possibility that senolytic drugs could be used to ablate A1 astrocytes as a potential
therapy in TBI. The following specific aims are proposed to test our hypothesis. Aim 1 would characterize
the induction, underlying mechanisms and role of A1 astrocytes in TBI. This would be achieved by: 1a.
Characterizing A1/A2 astrocyte induction and astrocyte transcriptome changes in the brain after TBI. 1b.
Determining the role of microglia in A1 astrocyte induction in the brain after TBI. 1c. Determining neurotoxic
ability of A1 astrocytes isolated from the brain after TBI. 1d. Establishing whether A1 astrocytes have a
critical role in long-term neuropathology and functional outcome following TBI. Aim 2 would determine the
therapeutic efficacy of targeting senescent A1 astrocytes and microglia as a potential therapy for TBI. This
would be achieved by: 2a. Determining the therapeutic efficacy of senolytic drugs to ablate senescent A1
astrocytes and senescent microglia and reduce neuropathology and functional deficits long-term after TBI.
2b. Establishing the therapeutic window for senolytic drug treatment in TBI. 2c. Determining the duration of
beneficial effects for senolytic drugs in TBI. The proposed research is highly innovative conceptually in
proposing a critical role of recently identified A1 astrocytes and senescent cells in TBI pathology and chronic
neuroinflammation. It is also highly innovative technically in the proposed use of a novel triple-knockout
mouse model of the three A1-inducing factors, RNA-seq for glial cell transcriptome profiling, and the
proposed use of recently identified senolytics as potential therapies to improve long-term outcome in TBI. If
successful, the studies would have high impact on the field as they could provide hope of a therapy that
could be used months or even years after TBI, where there is now no treatment options other than supportive
care.

Grant Number: 5R01NS122724-04
NIH Institute/Center: NIH
Principal Investigator: DARRELL BRANN