Fight Aging!

Amyloid-β is one of the forms of misfolded protein that accumulate in tissues with age, precipitating to form solid clumps and fibrils. This one forms in the brain and is associated with Alzheimer's disease. Amyloid levels are fairly dynamic, and their growth with age appears to be a slow failure of clearance mechanisms rather than a gradual accumulation. One of those discussed here in the past is the choroid plexus, a filtration system for cerebrospinal fluid. Here, however, is consideration of another failing mechanism, one that is more tightly bound to the degeneration of blood vessel tissues.

This is of interest because Alzheimer's risk is strongly correlated to blood vessel health. Further, the process of age-related degeneration in blood vessels is one for which the links to forms of cellular and molecular damage that cause aging are fairly well understood at this time: cross-links formed by metabolic waste degrade blood vessel elasticity, for example. Ways to effectively remove those cross-links, such as those envisaged as the end result of work underway at the SENS Research Foundation, should be broadly beneficial to brain health as well as other tissues.

In Alzheimer's disease, amyloid-β (Aβ) accumulates as insoluble plaques in the brain and deposits in blood vessel walls as cerebral amyloid angiopathy (CAA). The severity of CAA correlates with the degree of cognitive decline in dementia. The distribution of Aβ in the walls of capillaries and arteries in CAA suggests that Aβ is deposited in the perivascular pathways by which interstitial fluid drains from the brain. Soluble Aβ from the extracellular spaces of gray matter enters the basement membranes of capillaries and drains along the arterial basement membranes that surround smooth muscle cells toward the leptomeningeal arteries. The motive force for perivascular drainage is derived from arterial pulsations combined with the valve effect of proteins present in the arterial basement membranes.

Factors that affect cerebrovascular health, such as age and APOE genotype, alter both the structure of the blood vessels and the expression of the basement membrane proteins such that the efficiency of perivascular drainage of Aβ is reduced. As increasing amounts of Aβ become entrapped within the drainage pathways, it causes damage to the underlying vasculature, further reducing the functionality of the vessel and creating a feedforward mechanism by which increasing amounts of Aβ accumulate as CAA. Finally, diffusion of soluble Aβ and interstitial fluid through brain tissue is blocked by insoluble Aβ in the extracellular spaces, levels of soluble Aβ and other metabolites in brain parenchyma rise and dementia ensues.

The failure of perivascular clearance of Aβ may be a major factor in the accumulation of Aβ in CAA and may have significant implications for the design of therapeutics for the treatment of Alzheimer's disease.

Link: http://onlinelibrary.wiley.com/doi/10.1111/bpa.12159/full