Abstract 9- 1400-1415
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Dr. Nicole Schwab
Lili-Naz Hazrati (1,2), Nicole Schwab (1,2)
(1) The Hospital for Sick Children, Toronto, ON, Canada
(2) Department of Laboratory Medicine and Pathobiology, University of Toronto, Canada
Glial senescence (not tau) is the driver of post-concussive symptoms
Mild traumatic brain injury (mTBI) leads to chronic symptoms in some patients. Pathologically, mTBI is associated with chronic traumatic encephalopathy (CTE), a neurodegenerative disease characterized by hyperphosphorylated tau (p-tau) in neurons and astrocytes at the depths of cortical sulci. CTE has been proposed as the driver of these symptoms, despite many patients presenting with severe symptoms yet minimal pathology. It is known that low levels of p-tau are present in cognitively intact individuals, including ageing-related tau astrogliopathy (ARTAG), and that p-tau accumulates prior to a diagnosis of Alzheimer’s disease. We propose that examining changes beyond p-tau is critical to understand mTBI pathology.
The objective of this study is to identify novel pathological markers of mTBI which may explain clinical symptoms and allow for the development of therapeutic targets.
Using a brain bank of former professional athletes with mTBI history we used immunohistochemistry and gene expression analysis to show cellular senescence as a mechanism driving brain dysfunction after mTBI. Compared to controls, mTBI brains show widespread DNA damage (γH2AX) and cellular senescence in ependymal cells, astrocytes, and oligodendrocytes even in cases with no neuropathology. Gene expression analysis revealed upregulation of the senescence-associated secretory phenotype (SASP), a form of chronic low-level inflammation which has been proposed to drive cognitive dysfunction and proteinopathy. In a mouse model of mTBI, we have recapitulated these results and shown that eliminating senescent cells with senolytic therapy is beneficial.
mTBI brains are characterized by early ageing through cellular senescence, which may drive clinical symptoms and p-tau pathology.