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.

Associations of cerebrospinal fluid amyloidogenic nanoplaques with cytokines in Alzheimer’s disease

“…Future research should assess whether the nanoplaques and cytokines are also associated in serum samples. Moreover, studies on microvascular pathology, a common feature of AD [ 57 ], are another avenue for future research: MIP-1α receptors are highly expressed on brain microvessels and it has been hypothesised that MIP-1α binding could affect angiogenesis and blood-brain barrier permeability [ 58 – 60 ]. IL-8 has also been linked to angiogenesis and blood-brain barrier dysfunction [ 61 , 62 ].…”

Calcium Dyshomeostasis in Alzheimer’s Disease Pathogenesis

“…The pathogenesis of AD involves the massive extracellular deposition of amyloid-β (Aβ), forming cores of senile plaques in the brain parenchyma, and intracellular accumulation of the abnormally hyperphosphorylated tau proteins, forming neurofibrillary tangles (NFTs) [ 2 , 8 , 9 , 10 , 11 ]. Aβ and NFTs induce the loss of neurons and synaptic density by enhancing the inflammation process, oxidative stress and the occurrence of cerebral microvascular disease [ 12 ]. Aβ plaque also promotes the senescence of neural stem/progenitor cells by affecting forebrain and hippocampal neurogenesis [ 13 ].…”

“…Aβ plaque also promotes the senescence of neural stem/progenitor cells by affecting forebrain and hippocampal neurogenesis [ 13 ]. Emerging evidence suggests the existence of additional molecular pathophysiological pathways, including axonal disintegration [ 14 ], synaptic dysfunction and degeneration [ 15 ], innate immune responses and neuroinflammation [ 16 , 17 ], vascular dysregulation [ 12 , 18 ], and brain metabolic dysfunction [ 19 ] across the different stages of AD.…”

Network-driven anomalous transport is a fundamental component of brain microvascular dysfunction

“…This suggests that the uncovered anomalous transport mechanisms are general, even if the parameter values and pre-factors of scaling laws may be slightly dependent on the specific assumptions in our blood flow computational scheme. Thus, the variability of the network architecture, including differences between brain areas and between species 39,66 , differences due to long term vessel remodeling in hypoxia, aging or disease 61,62,67 , as well as passive or active diameter variations resulting from changes in pressure, blood flow, brain autoregulation and/or neurovascular coupling 2,6,21,68 , is unlikely to fundamentally alter the nature of the statistical laws that we have derived. Blood is ultimately transported in the brain capillary network, the structure of which is highly similar between species 39 , so that velocity fluctuations are expected to follow similar distributions as described here.…”