Our objective is to investigate the clearance of interstitial fluid from the brain and improve our understanding of the accumulation of proteins in the walls of the vasculature in ageing brains. There is significant evidence suggesting that pathologies associated with the clearance of amyloid-? from the brain contributes to the occurrence of Alzheimer?s disease. Our hypothesis is that the interstitial fluid, driven by hydrodynamic forces exerted by the pulsation of the arterial basement membranes, transports amyloid-? along the perivascular spaces outside the cerebral arteries. We have developed a preferential transport theory where the driving forces stem from the superposition of forward- propagating waves and their associated reflections along the arterial basement membranes. Perivascular pathways for lymphatic drainage have been identified in both experimental animals and in humans. Interstitial fluid and solutes enter bulk flow pathways in capillary and artery walls to drain to the cervical lymph nodes. However, it has also been shown that there is transport of the cerebrospinal fluid in the opposite direction as evidenced by the injection of tracers into the cisterna magna. As part of this proposal, we seek to clarify these seemingly contradictory results. Central to this proposal is the use of multi-photon microscopy to measure the transport of fluid along the arterial perivascular spaces. The effects of waveform pulsatility and pathway geometry on the fluid transport will be elucidated by studying mouse models with and without cerebral amyloid angiopathy. Our theory predicts that the arterial wall deformations drive transport. Therefore, we propose to monitor the deformation of the arterial walls using the third harmonic generation obtained from multi-photon microscopy. This novel, label-free imaging methodology is ideal for capturing the arterial wall motion. We will measure the time-dependent radial position of the various compartments in multiple places along the vascular hierarchy by including some of the first few branches off of the vertically oriented arterioles and venules. The in vivo data will be used to refine and validate our preferential transport theory for drainage through the basement membranes. Once validated, this theory can be used to provide key insights on the physiological parameters that govern amyloid-? clearance and accumulation in the perivascular space.
Alzheimer?s disease is a leading cause of death in the United States and a significant burden on the nation?s health care system. It is a debilitating illness that affects millions of people ? and their families ? worldwide. The proposed work seeks to understand the transport mechanisms of protein molecules in the brain and how their clearance may fail in aging brains that develop this disease.