Perivascular lymphatic drainage and solute clearance:
R. Carare 2015, R.O.Carare@soton.ac.uk
Our working hypothesis is that the deposition of amyloid plaques in the human brain with age and Alzheimer’s disease reflects a failure of elimination of Aβ from the brain. Several mechanisms for the elimination of Aβ from the brain have been defined. These include degradation by enzymes such as neprilysin , receptor-
As arteries age, lymphatic drainage becomes less efficient  and Aβ is deposited in basement membranes of arteries and capillaries as cerebral amyloid angiopathy (CAA), which further impairs perivascular lymphatic drainage . APOE ε4 is also associated with impaired perivascular lymphatic drainage as demonstrated in mice expressing human ApoE ε4 .
As a result of the failure of elimination of Aβ from the brain associated with ageing of cerebral arteries and CAA there is loss of homoeostasis of the extracellular environment in the brain as reflected in the rise of soluble Aβ in Alzheimer’s disease . It is likely that there is also failure of elimination of soluble metabolites other than Aβ adding further to the loss of homoeostasis of the neuronal environment. The association of CAA with accumulation of fluid in the subcortical white matter reported after recent therapeutic trials in Alzheimer’s disease suggests that drainage of fluid is ultimately impaired [16, 17].
We are working in an interdisciplinary manner to demonstrate that changes in extracellular matrix and artery walls due to age, genotype, diet or different patterns of innervation or branching of blood vessels could have a marked effect upon the extracellular environment of brain tissue leading especially to failure of elimination of Aβ from the extracellular space but also to failure of elimination of other metabolites and loss of homeostasis. Our mission is to clarify the exact factors that are responsible for efficient drainage along basement membranes of capillaries and arteries in order to identify new therapeutic targets for cerebral amyloid angiopathy and Alzheimer’s disease.