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Fig. 1 | Molecular Neurodegeneration

Fig. 1

From: The role of inflammasomes in vascular cognitive impairment

Fig. 1

A schematic diagram illustrating the possible pathological mechanisms of VCI. Cardiovascular disease is major contributor to early cerebral blood flow reduction in the disease progression of VCI. These conditions include heart disease (i.e. coronary artery disease and arrhythmias) that impairs the ejection of blood into the blood circulation; and small and large vessel diseases (i.e. atherosclerosis and arteriosclerosis), which narrow the vascular lumen and impede blood flow. Neuronal loss results in reduced production of angiogenesis regulators, leading to neurovascular unit uncoupling. These conditions converge to cause chronic cerebral hypoperfusion that reduces delivery of glucose and oxygen to the brain leading to decreased energy (i.e. ATP) production, resulting in bioenergetic impairment. Reduced ATP levels initiate a series of pathogenic molecular and cellular mechanisms. Firstly, the function of ATP-dependent transporters (i.e. Na+/K+ ATPase) are impaired leading to ionic imbalance (i.e. Na+ and Ca2+ influx, and K+ efflux) across the plasma membrane resulting in anoxic depolarization within neurons causing excitotoxicity. Moreover, increased levels of intracellular Ca2+ activate a wide variety of calcium-dependent ROS generating pathways in the mitochondria and cytosol contributing to oxidative stress. Finally, neuroinflammation is activated as stressed or injured cells release DAMPs that bind to PRRs to induce an inflammatory response. Under CCH, these molecular mechanisms influence each other within different cell types that result in the following pathogenic cellular mechanisms: glial activation, BBB dysfunction, cell death and demyelination. As pathogenic cellular mechanisms accumulate, they synergistically drive further damage eventually causing structural damage such as white matter lesions, microinfarcts and hippocampal atrophy. Each of these structural changes cause disruption to the neuronal network and functional connectivity that eventually leads to cognitive decline. Abbreviations: VCI, vascular cognitive impairment; ATP, adenosine triphosphate; ROS, reactive oxygen species; DAMPs, damage-associated molecular patterns; CCH, chronic cerebral hypoperfusion; BBB, blood brain barrier

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