R Carare - Physiology of Perivascular drainage of the brain and how it is affected by advancing age

Fluid and soluble waste drain from all organs of the body to regional lymph glands. For organs such as the lung and liver, there are clearly defined channels along which the fluid and waste products drain. However, there are no such well-defined channels to drain fluid and waste products from the brain; instead, the drainage pathways are very narrow and confined to the walls of the arteries that supply the brain. This drainage pathway for waste products from the brain has received little attention in the past but its importance is becoming increasingly recognised because of its potential role in the decline of mental and psychological health. There are many unknown factors concerned with the perivascular drainage pathways from the normal brain and they need to be resolved before measures can be taken to maintain normal mental health in the elderly. One of the important features of the ageing brain is the accumulation of an insoluble protein, amyloid-beta, within the brain substance. Our previous studies have shown that in normal young individuals, amyloid-beta drains out of the brain along the narrow pathways within the walls of brain arteries. However, as people become older, there is a failure of the drainage of amyloid-beta; it then accumulates in the brain and disturbs its normal biology. This is the reason why we are so interested in the drainage pathways. Our project consists of three parts in which we investigate the normal drainage of waste products from the brain. With the information derived from the study, we can start to devise ways of improving the drainage of amyloid-beta from the brains of older people. 1] We will determine the force that drives fluid and waste products such as amyloid-beta out of the brain along the walls of arteries. In order to do this, we will inject a tracer substance that emits a fluorescent glow and then observe its progress along the walls of arteries in the brain using a two photon microscope. This microscope has been developed for viewing arteries in the brain and, by taking photographs at very short intervals, we will be able to test our hypothesis that the force driving fluid and waste products out of the brain is derived from the pulsations in the arteries. By using a drug, a beta-blocker, we will reduce the strength of the pulsations and measure the effect on the drainage of waste products from the brain. The main reason for using the beta-blocker is that it mimics the effects of ageing in brain arteries. As people get older, their arteries become stiffer and the strength of the pulsations reduces, preventing the elimination of amyloid-beta from the ageing brain. 2] The width of the drainage pathway by which fluid and waste products are eliminated in the brain along the walls of arteries is only 100-150nm thick (1nm equals one billionth of a meter). It is important, therefore, to know how large a protein molecule or particle can pass along the drainage pathway. If the proteins are too large, they may block the drainage pathway and this would prevent waste products from leaving the brain. We will inject particles up to 20nm in diameter into the brain to test the capacity of the drainage system. The results of this study will be combined with those in the previous study to determine how the capacity of the drainage system decreases with age in normal individuals. 3] We will study the composition of the drainage pathway itself. The drainage pathway is composed of a complex mixture of proteins. We know that the appearance of the layer under the microscope changes with age, so now we plan to determine the chemical changes that occur in this layer with age. By using innovative techniques of analysis (proteomics), the chemical structure of the normal pathway by which fluid and waste products drain from the brain will be revealed and furthermore, we will document the changes that occur with increasing age.