Measuring impairment of extracellular solute transport in Alzheimer's disease

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Project summary/abstract The extracellular space (ECS) of the brain consists of a highly interconnected network of narrow tunnel and sheet-like structures with width of 10-80 nm. Perivascular spaces surrounding blood vessels connect with the ECS and act as conduits for transport of solutes throughout the parenchyma and to the CSF at the surface of the brain. Nutrient delivery to tissues, clearance of toxic protein aggregates and therapeutic delivery to targets require transport through the ECS and considerable uncertainty exists regarding the rates and mechanisms of transport in vivo. Specifically, neither the rate, direction or regulation of solute transport in the perivascular spaces are well understood. Recently, we demonstrated that multiphoton fluorescence recovery after photobleaching (MP-FRAP) of exogenous fluorophores introduced into the ECS can be used to directly measure solute transport rates deep within the brain parenchyma in vivo. Experiments to be performed here will adapt this technique to measure the rates and direction of perivascular solute transport in mouse brain and thereby resolve basic questions regarding the physiology of these spaces. In Alzheimer’s disease (AD), amyloid plaques form in the parenchyma and around blood vessels, causing extensive changes in structure and function of the surrounding glia. The consequences of these changes for transport of solutes in the perivascular space remain largely unknown and we will utilize AD model mice to determine if deposition of Aβ around vessels impairs perivascular solute movement. It is hoped that these experiments will lead to a quantitative and well substantiated understanding of perivascular extracellular transport in the brain, and suggest approaches for enhancing endogenous clearance mechanisms and improving therapeutic delivery.