Friday, May 3, 2024
5/3/2024
Summary Abstract Alzheimer's disease (AD) is the leading cause of dementia worldwide and is characterized by the formation of senile plaques, extracellular aggregates composed of the protein Aß that begin forming more than a decade before the onset of clinical symptoms. Aging is the strongest risk factor for the development of AD, yet the factors that render the aging brain vulnerable to Aß deposition remain unknown and no treatments exist that can prevent or reverse this process in the aging brain. We have recently defined a brain-wide perivascular network, termed the `glymphatic' system that facilitates the exchange of interstitial fluid and cerebrospinal fluid, facilitating the clearance of interstitial wastes including Aß from the brain. 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. Genetic deletion of AQP4 slows Aß clearance from the brain and accelerates Aß plaque deposition in a transgenic mouse model of AD. We have observed that perivascular AQP4 localization is disrupted in both the aging mouse and human cortex, and that in the human cortex, loss of perivascular AQP4 localization is associated with worsening Aß plaque burden and AD. Based on these findings, we propose that loss of perivascular AQP4 localization in the aging brain impairs interstitial Aß clearance and promotes Aß plaque formation. In this proposal, we will use a transgenic mouse model that lacks perivascular AQP4 localization to determine whether loss of AQP4 localization slows interstitial Aß clearance. We will then use an in vivo viral transfection approach to test whether upregulation of the AQP4-M23 variant, which is upregulated in the aging brain, disrupts perivascular AQP4 localization and impairs glymphatic pathway function. These two approaches will then be used to determine whether loss of perivascular AQP4 localization, including by AQP4-M23 upregulation, promotes Aß plaque deposition in a mouse model of AD that spontaneously develops Aß plaques. Using MRI-based imaging of glymphatic function, we will evaluate whether regions of impaired glymphatic function promote local Aß plaque deposition. If validated, then these studies may provide a mechanistic basis for the vulnerability of the aging brain to Aß aggregation, including an explanation for the vulnerability of certain brain regions to this process early in the disease course. These findings may identify a new therapeutic approach to preventing these processes in the aging brain.
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