Aberrant PTEN signaling in chronically activated microglia drives tau pathology, neurodegeneration and cognitive decline following repetitive brain injury - Repetitive mild TBI (r-mTBI) can induce neurological impairment years after injury, increasing the risk for Alzheimer’s Disease
(AD). No suitable treatments have been developed to rescue the long-term consequences of TBI. Advancing our understanding of
the mechanisms driving the chronic effects of r-mTBI is critical, as this could lead to the identification of novel therapies. Microglia
mediated neuroinflammation is a common feature of TBI and AD. Experimental evidence suggests that neurodegeneration and
cognitive deficits are associated with the maladaptive transformation of microglia from an early neurorestorative phenotype to a
dysfunctional and chronically activated proinflammatory state. Factors governing the persistence of these neuroinflammatory
responses in the chronic sequelae of TBI remain elusive. We have established a WT mouse model that recapitulates many of the
features of human r-mTBI and thus represents a translationally relevant preclinical platform to interrogate these factors. Having
established this r-mTBI model (and given the role of tau as a pathognomonic lesion of TBI), we generated microglial transcriptomic
profiles in human Tau Knock In (TauKI) mice at a range of timepoints post-injury. Firstly, when we compared microglial responses
in TauKI vs WT mice, we revealed an increase in significant gene transcripts between r-mTBI and sham microglia by 3 to 9-fold at
chronic timepoints. In the TauKI model, we reveal deficits in bioenergetics, cytokine signaling, lipid metabolism, and a pro-
inflammatory signature of chronically activated microglia, which appear to be influenced by the activation of Phosphatase and
Tensin Homolog (PTEN) signaling, and this correlated with TBI dependent Tau pathology. PTEN is a lipid phosphatase that
antagonizes PI3K signaling, a critical node vital for regulating cell survival, energy bioenergetics and inflammation. PTEN is highly
expressed in myeloid cells, and its dysregulation can trigger the activation of neuroinflammatory responses. PTEN activation has
been reported to occur early in tauopathy models, and its inhibition, dampens microglial activation, reduces synaptic phagocytosis
by microglia, and preserves neuronal integrity. We thus hypothesize that PTEN activation is a mediator of chronically activated
microglia and their dysfunctional activities, and a driver of tau seeding and pathogenesis, such that genetic deletion of PTEN in
microglia will mitigate the deleterious effects of chronic microglial activation on tau pathology and long-term TBI outcomes. To
begin to address this, we developed a Cre-LoxP model that specifically deletes PTEN in myeloid cells between 2.5 to 3.5 mo post-
injury and revealed rescue of pro-inflammatory microglial responses after r-mTBI. In this new proposal, we plan to expand on
this work, using an improved tamoxifen inducible model on a human TauKI background that deletes PTEN signaling in microglia,
and not other myeloid cells. We will explore the optimal time-window of intervention (early vs delayed) and generate a detailed
longitudinal time-course of neurobehavior, microglial phenotype and function, tau seeding/pathogenesis and neuropathological
outcomes after r-mTBI. We will also use a single cell RNAseq mining approach to compare TBI-dependent responses in the
presence or absence of PTEN deletion to identify the distinctive states of microglia and reparative mechanisms that drives their
favorable outcomes. Our goal is to identify molecular mechanisms driving the transformation of chronic microglia into a
proinflammatory and neurotoxic phenotype that contribute to tauopathy, neurodegeneration and cognitive deficits, in order to
develop new and effective delayed therapeutic interventions for TBI and AD.
