The role of PPAR? in astrocyte pathobiology after exposure to repetitive mild traumatic brain injury - Repetitive mild traumatic brain injury (r-mTBI) can induce neurological damage many years after the cessation of injury,
increasing the risk for ADRD. No disease-modifying treatment strategies have been developed to mitigate the long-term
consequences of r-mTBI. There is an urgent need to advance our current understanding of the cellular mechanisms driving
the cascade of secondary injury events, as this could lead to the identification and development of novel therapeutics.
Astrocytes play an important role in these secondary injury events. After acute insult, they undergo a dramatic transcriptomic
and morphological transformation. Reactive astrocytes can be polarized into different states adopting neuroprotective or
neurotoxic properties that can influence brain recovery. Neuroprotective astrocytes can serve to create a physical barrier to
limit the spread of damage, preventexcitotoxicity, boost metabolic support for neurons, and release trophic factors to promote
neurorepair. While neurotoxic astrocytes can take a dual role of neuroinflammation and glial scar formation that inhibits
axonal regeneration and promotes neuronal damage, and this can be accompanied by loss of their constitutive supportive
roles. Our knowledge of the mechanisms that regulate astrocyte phenotypes and responses in the healthy brain or after brain
injury is lacking. To address this, we established a mouse model of r-mTBI that recapitulates many of the features of human
TBI and thus represents a translationally relevant preclinical platform. Using this model, we generated a molecular library of
astroglia gene profiles, at a range of timepoints post-injury that provides a unique and detailed time-course of the astroglia
response to TBI. Particularly, we reveal deficits in cellular metabolism, oxidative stress and a proinflammatory signature of
astroglia, which appears to be influenced by the loss of constitutive PPAR? signaling in astrocytes. PPARγ is highly expressed
in glial cells and plays a vital constitutive role in regulating cell metabolism, bioenergetics, cell survival and immune function.
Treatment with a PPARγ agonist has shown efficacy in restoring behavioral outcomes and rescuing astroglia pathobiology in
our r-mTBI model. Because multiple cell types express PPARγ receptors, PPARγ ligands lack the specificity needed to target
astroglia specific PPARγ signaling in vivo. In this proposal, we plan to clarify the constitutive role of PPARγ in regulating
astroglial responses in the healthy brain and in the context of TBI, and demonstrate whether astroglia specific PPARγ
activation mitigates TBI mediated astroglia activation, inflammation, neurodegeneration and functional outcomes. We will
achieve this by utilizing a tamoxifen inducible mouse model that specifically targets PPARγ activation in astrocytes. We will
induce PPARγ activation inastrocytes using three therapeutic time-windows (i.e., pre-injury, early and delayed), and examine
functional and pathobiological outcomes, scRNAseq profiles and functional activities of astroglia at 6 mo post-injury. In our
scRNAseq study, we will compare TBI-dependent responses in the presence or absence of PPARγ activation to reveal
astroglia-specific targets that correlate with favorable outcomes at the optimaltime-window of treatment, and represent novel
therapeutic and translational targets. Our goal is to clarify the role of PPARγ as a regulator of astroglia pathobiology in the
chronic sequelae of TBI and identify reparative mechanisms in astrocytes driving favorable outcomes that can be explored as
novel astrocyte specific targets in future work, not only in TBI but ADRD where astrocyte pathobiology is a critical contributor.
