Deposition of proteins in the perivascular drainage pathways in the walls of cerebral arteries is recognised as Protein Elimination Failure Angiopathy (PEFA), as in cerebral amyloid angiopathy (CAA) and cerebral autosomal dominant arteriopathy and leukoencephalopathy (CADASIL).
Here we aim to investigate the role of impaired drainage of interstitial fluid in PEFA. Whereas the volume of the extracellular space in grey matter in the brain is tightly controlled, fluid accumulates and expands extracellular spaces of white matter in amyloid related imaging abnormalities.
Aquaporin 4 (AQP4) is the main water channel in the CNS and our pilot data shows that (i) it has a lower expression in the human/rodent white matter compared to grey matter, suggesting a deficiency in water homeostasis in the white matter and (ii) its inactivation results in a blockage of the diffusing interstitial fluid through the glia-pia basement membrane (MB). The pattern of intracerebral injections of fluorescent soluble Aβ40 in the corpus callosum of mice demonstrates that soluble Aβ enters the BM of vessels. Soluble tracers injected in the grey matter enter only BM of capillaries and arteries, with tracers entering the walls of veins only in ageing mice or in the presence of immune complexes.
The key aspects of the proposed study are: (i) to identify the pathways for clearance of soluble Aβ from the white matter; (ii) to demonstrate how blockage of AQP4 disrupts perivascular clearance, and (iii) to characterise the fine morphology of peridural recently described lymphatic vessels. Using our precise and validated imaging techniques, we will analyse the exact diffusion of injected Aβ into the white and gray matter brains of Wistar and Spontaneously Hypertensive Stroke Prone (SHRPS) rats. Facilitating perivascular intramural drainage from the ageing brain may play a significant role in the prevention of CAA, and Alzheimer’s Disease (AD), and may enhance the efficacy of immunotherapy for AD.