? DESCRIPTION (provided by applicant): Traumatic brain injury (TBI), a leading cause of death and disability worldwide, is an established risk factor for the development of dementia and Alzheimer's disease later in life. Neurofibrillary tangles, aggregates composed of the intracellula protein tau, are one of the hallmarks of the Alzheimer's disease brain and are thought to cause the death of neurons in this condition. Although these tau aggregates are a common feature of the brain after TBI, the changes that occur in the brain after traumatic injury that make it vulnerable to tau aggregation remain undefined and no treatments exist that can prevent the development of neurodegeneration after TBI. We have recently defined a series of paravascular channels throughout the brain that provide an avenue for the brain to clear wastes from between neural cells. Fluid movement along these pathways and through the brain interstitium is facilitated by the water channel aquaporin-4 (AQP4) which is expressed in a highly polarized manner in astrocyte membranes that directly face the brain vasculature. When this channel is knocked out, fluid movement along these paravascular pathways is lost and the clearance of wastes from the brain interstitium is markedly reduced. Tau, the protein that chiefly makes up neurofibrillary tangles yet is released into the interstitium under resting conditions, is cleared from the brain along these paravascular pathways, while interstitial solute clearance along these paravascular pathways is slowed after TBI. At the same time, AQP4, which is normally localized to vessel-facing astrocyte processes, loses its polarization. Based on these findings, we propose that the loss of perivascular AQP4 polarization after TBI impairs interstitial tau clearance, promoting tau aggregation and neurodegeneration after TBI. In this proposal, we will first utilize a transgenic mouse model to determine whether loss of perivascular AQP4 localization impairs interstitial tau clearance. We will then use an in vivo viral transfection approach to test whether upregulation of the AQP4-M1 variant after TBI causes the loss of perivascular AQP4 polarization after TBI. We will then use these approaches in a transgenic mouse line exhibiting spontaneous age-related neurofibrillary tangle formation to test whether loss of perivascular AQP4 polarization and impairment of interstitial tau clearance promote tau aggregation and neurodegeneration after TBI. If validated, then these studies may provide a mechanistic basis for the vulnerability of the post-traumatic brain to tau aggregation and neurodegeneration, and may identify a new therapeutic approach to preventing the development of neurodegeneration after TBI.
|Effective start/end date||9/1/15 → 6/30/20|
- National Institutes of Health: $343,899.00
- National Institutes of Health: $322,524.00
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