ABSTRACT
Traumatic brain injury is a risk factor for cognitive impairment and dementia, such as Alzheimer’s disease (AD)
and frontotemporal dementia (FTD), particularly in the aged populations. Nevertheless, the mechanisms by
which aging exacerbates cognitive deficits after brain injury are not fully understood. Human brain imaging
studies reported the signs of microglial activation in the thalamus that correlate with cognitive deficits. Our
preliminary studies using a local microglia depletion in mice have discovered that thalamic microglia activation
is required for cognitive deficits after brain injury. In the middle-aged mice, cognitive deficits after brain injury
were exacerbated and accompanied by dysregulated responses of microglia and accumulation of AT8-positive
phosphorylated tau proteins (p-tau). Recent studies have reported that one of the aging-associated molecular
signatures in the mouse brain is an increased interleukin-33 (IL-33) expression in oligodendrocytes. Indeed, IL-
33 expression was increased in thalamic oligodendrocytes. Notably, blocking of IL-33 in the aging thalamus
ameliorated aging-associated exacerbation of cognitive deficits. These findings suggest that aging-associated
changes in the thalamic environment and microglial responses contribute to p-tau accumulation and
exacerbated cognitive deficits in aged mice after cortical injuries. Thus, in the proposed study, we will test our
hypothesis that aging-associated oligodendrocyte-derived IL-33 exacerbates cognitive impairment
after cortical injury by driving microglial dysfunction and tau pathology in the thalamus. In Aim 1, we
will further evaluate aging-associated changes in thalamic pathology and cognitive impairment after cortical
injuries and determine the effects of thalamic microglial depletion and neuronal tau deletion on exacerbated
cognitive impairment. In Aim 2, we will investigate the requirement of oligodendrocyte-microglial IL-33
signaling in aging-associated microglial dysfunction, p-tau accumulation, and worsening cognitive impairment
after cortical injuries. In Aim 3, we will examine the mechanisms by which aging-associated IL-33 signaling
alters microglial responses after cortical injuries. Together, this study will determine the mechanisms by which
oligodendrocyte-microglia IL-33 signaling induces microglial dysfunction, p-tau accumulation, and cognitive
impairment relevant for AD/ADRD.
