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 A? 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 A? 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 A? 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 A? clearance from the brain and accelerates A? 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 A? plaque burden and AD. Based on these findings, we propose that loss of perivascular AQP4 localization in the aging brain impairs interstitial A? clearance and promotes A? 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 A? 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 A? plaque deposition in a mouse model of AD that spontaneously develops A? plaques. Using MRI-based imaging of glymphatic function, we will evaluate whether regions of impaired glymphatic function promote local A? plaque deposition. If validated, then these studies may provide a mechanistic basis for the vulnerability of the aging brain to A? 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.
Alzheimer's disease (AD) is the leading cause of dementia worldwide and is characterized by the formation of A? plaques between the brain's cells as the brain ages. However, the changes that occur in the aging brain that make it vulnerable to A? aggregation are not known. This proposal will investigate whether the brain's waste clearance system fails as the brain ages, leading to the buildup of A? aggregates that drive Alzheimer's disease. These studies will help to define why the aging brain is so uniquely susceptible to the development of Alzheimer's disease, and may lead to the development of new treatments that prevent these events in the brains of people as they age.
| Simon, Matthew J; Murchison, Charles; Iliff, Jeffrey J (2018) A transcriptome-based assessment of the astrocytic dystrophin-associated complex in the developing human brain. J Neurosci Res 96:180-193 |
| Boespflug, Erin L; Iliff, Jeffrey J (2018) The Emerging Relationship Between Interstitial Fluid-Cerebrospinal Fluid Exchange, Amyloid-?, and Sleep. Biol Psychiatry 83:328-336 |
| Mestre, Humberto; Hablitz, Lauren M; Xavier, Anna Lr et al. (2018) Aquaporin-4-dependent glymphatic solute transport in the rodent brain. Elife 7: |
| Goodman, James R; Adham, Zachariah O; Woltjer, Randall L et al. (2018) Characterization of dural sinus-associated lymphatic vasculature in human Alzheimer's dementia subjects. Brain Behav Immun 73:34-40 |
| Simon, Matthew J; Wang, Marie X; Murchison, Charles F et al. (2018) Transcriptional network analysis of human astrocytic endfoot genes reveals region-specific associations with dementia status and tau pathology. Sci Rep 8:12389 |
