Award details

Physiology of perivascular drainage of the brain and how it is affected by advancing age

Reference	BB/K015540/1
Principal Investigator / Supervisor	Professor Roxana Carare
Co-Investigators / Co-Supervisors	Professor Simon Schultz
Institution	University of Southampton
Department	Clinical and Experimental Sciences
Funding type	Research
Value (£)	604,304
Status	Completed
Type	Research Grant
Start date	01/09/2013
End date	31/08/2017
Duration	48 months

Abstract

Most organs in the body possess lymphatics by which proteins drain to lymph nodes for maintenance of immune competence and homoeostasis. The brain has no such traditional lymphatics but tracer studies in experimental animals have shown that interstitial fluid drains from the brain along the cerebrovascular basement membranes (BM) to regional lymph nodes in the neck. The same perivascular lymphatic drainage route is present in human brain as shown by the pattern of deposition of amyloid-beta (Abeta) in cerebral amyloid angiopathy (CAA) in the normal elderly brains. The aims of this project are to: 1] Test the hypothesis that the motive force for perivascular drainage from the brain is derived from pulsations in cerebral arteries. We will directly observe the passage of tracers along BM in cerebral artery walls by Two Photon Microscopy. The effects of reduced vascular pulsations upon the efficiency of perivascular drainage will be observed following administration of beta-blockers. Data from this study are important because ageing cerebral arteries lose their elasticity and the amplitude of pulsations is reduced. Reduction in the motive force for drainage may result in deposition of Abeta in artery walls with age. 2] Define the size of molecules or particles that can pass along the perivascular drainage route. Preliminary studies suggest that particles of 20nm may deposit in BMs and temporarily obstruct the perivascular drainage route. So, nanoparticles 10-20nm will be injected to assess how efficiently they are drain along perivascular pathways. Data derived from the study will help to establish the capacity of the normal perivascular drainage pathway. 3] Test the hypothesis that changes in the morphology of BMs in cerebral artery walls with age reflect changes in their proteomics. The data will be essential for future planning of strategies to facilitate the drainage of solutes, from the ageing brain.

Summary

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.

Impact Summary

The main groups who will benefit from the results of the present proposal will be other researchers in the fields of neuroimmunology and biogerontology; finally, and probably the most important group, will be the elderly population for whom there is no fully developed and successful strategy for facilitating the removal of metabolic waste along the ageing cerebrovascular system. Research into the neurophysiology of ageing moves forward on a broad front, ranging from genetics to therapy. As a basis for development in these fields, it is essential to have a firm understanding of the normal brain and its functions. Our research will help to clarify the normal physiology of drainage pathways for fluid and solutes from the brain and the effects that age has upon these pathways. It is increasingly recognised that the failure of elimination of amyloid-beta (Abeta) with increasing age is a major factor in the accumulation of Abeta in the brain and in the walls of cerebral blood vessels in ageing, contributing to cognitive decline. A number of mechanisms for the elimination of Abeta from the brain have been identified but the interrelationship between these mechanisms has not been firmly established. From previous animal experiments and observations in human brains, it appears that perivascular drainage of Abeta along the walls of cerebral arteries is a major route for the elimination of Abeta that fails with age. Establishing the normal physiology of perivascular drainage and the effects of age upon this pathway will form the foundation upon which future research can be based. For example: defining the molecular genetics of basement membranes in blood vessel walls may become an essential step in identifying populations who are most at risk of cognitive decline and for whom early therapy would be beneficial. Furthermore, the genes involved in the organisation and branching patterns of cerebral arteries during development may prove to be an important index to future failure of perivascular drainage of solutes, such as Abeta, from the ageing brain. Little is currently known about the role of perivascular lymphatic drainage of the brain in neuroimmunological reactions. Establishing the normal physiology of perivascular drainage would form a basis for future studies on the drainage of antigens, be they brain antigens or proteins derived from infecting viruses, to regional lymph nodes. The picture of how immunological reactions develop in the brain is incomplete at the present time because the exact roles of lymphatic drainage of the brain and the regional lymph nodes has not been fully characterised. The results of our studies should form a firm basis upon which to build future research in neuroimmunology. We hope that within the 3-5 years enough will be known about the physiology of lymphatic drainage of the brain to embark upon devising therapies that facilitate the perivascular elimination of Abeta from the brain for increasing the well-being and delaying the onset of cognitive decline in the elderly.

Committee	Research Committee A (Animal disease, health and welfare)
Research Topics	Ageing, Neuroscience and Behaviour
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

I accept the terms and conditions of use (opens in new window)

export PDF file

back to list new search