Microvascular Alterations in Alzheimer's Disease

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder associated with continual decline in cognition and ability to perform routine functions such as remembering familiar places or understanding speech. For decades, amyloid beta (Aβ) was viewed as the driver of AD, triggering neurodegenerative processes such as inflammation and formation of neurofibrillary tangles (NFTs). This approach has not yielded therapeutics that cure the disease or significant improvements in long-term cognition through removal of plaques and Aβ oligomers. Some researchers propose alternate mechanisms that drive AD or act in conjunction with amyloid to promote neurodegeneration. This review summarizes the status of AD research and examines research directions including and beyond Aβ, such as tau, inflammation, and protein clearance mechanisms. The effect of aging on microvasculature is highlighted, including its contribution to reduced blood flow that impairs cognition. Microvascular alterations observed in AD are outlined, emphasizing imaging studies of capillary malfunction. The review concludes with a discussion of two therapies to protect tissue without directly targeting Aβ for removal: (1) administration of growth factors to promote vascular recovery in AD; (2) inhibiting activity of a calcium-permeable ion channels to reduce microglial activation and restore cerebral vascular function.

Keywords: Alzheimer's disease; TRPM2; amyloid hypotheses; angiogeneis; growth factors; imaging; microvasculature; vasculature.

Figure 1

Diagram of healthy and Alzheimer's brain vasculature. (A) Diagram of healthy brain vasculature. Penetrating arteries (red) and veins (blue) are connected via a capillary mesh (gray). (B) Diagram of Alzheimer's brain vasculature. Deposition of amyloid (yellow dots) in the vascular bed causes vascular dysfunction and loss in AD, with proliferation of vessels around missing vasculature (Meyer et al., 2008). String vessels (black) with no blood cells form as endothelial cells undergo apoptosis. Neutrophils (purple dots) stall a small portion (~2%) of capillaries, reducing blood flow in the network. Penetrating vessels have a tortuous shape, with a tendency to decrease in diameter with aging in AD (Dorr et al., 2012). Capillaries been reported to increase (trending) in diameter in APP/PS1 mice (Lu et al., 2019), experience swelling in APP23 mice (Meyer et al., 2008), decrease in diameter in P301L tau mice (Bennett et al., 2018), and to form “string” vessels with no flow or blood cells in humans (Hunter et al., 2012). Tissue undergoes atrophy, causing vascular shrinkage and functional brain deficits such as memory loss.