An endothelial link between the benefits of physical exercise in dementia

Abstract

The current absence of a disease-modifying treatment for Alzheimer's disease (AD) and vascular cognitive impairment and dementia (VCID) highlights the necessity for investigating the benefits of non-pharmacological approaches such as physical exercise (PE). Although evidence exists to support an association between regular PE and higher scores on cognitive function tests, and a slower rate of cognitive decline, there is no clear consensus on the underlying molecular mechanisms of the advantages of PE. This review seeks to summarize the positive effects of PE in human and animal studies while highlighting the vascular link between these benefits. Lifestyle factors such as cardiovascular diseases, metabolic syndrome, and sleep apnea will be addressed in relation to the risk they pose in developing AD and VCID, as will molecular factors known to have an impact on either the initiation or the progression of AD and/or VCID. This will include amyloid-beta clearance, oxidative stress, inflammatory responses, neurogenesis, angiogenesis, glucose metabolism, and white matter integrity. Particularly, this review will address how engaging in PE can counter factors that contribute to disease pathogenesis, and how these alterations are linked to endothelial cell function.

Keywords: Alzheimer’s; dementia; endothelium; exercise; vascular cognitive impairment.

Figure 1.

Summary of the effects of lifestyle factors on cognition and how physical exercise (PE) modifies them. Cardiovascular risk factors have the common effect of disrupting endothelial cell function, while poor sleep impacts white matter integrity and clearance of toxic proteins. PE has been shown to decrease risk of developing vascular risk factors and improve quality of sleep, both of which decrease the likelihood of cognitive decline. CVD: cardiovascular disease; NO: nitric oxide; eNOS: endothelial nitric oxide synthase.

Figure 2.

Effects of physical exercise (PE) on various molecular phenomena including neurorepair, clearance, glucose metabolism, oxidative stress, and inflammation. ERK: extracellular signal-regulated kinases; Akt: protein kinase B; PI3K: phosphatidylinositol 3-kinase; GSK-3β: glycogen synthase-3β; SIRT3: sirtuin 3; SOD: superoxide dismutase; HIF-1α: hypoxia-inducible factor 1α; INF-γ: interferon gamma; IL-1β: interleukin 1β; TNF-α: tumor necrosis factor alpha; IL-6: interleukin 6; COX-2: cycloxygenase 2; VCAM-1: vascular cell adhesion molecule 1; ICAM-1: intracellular adhesion molecule 1.

Figure 3.

Benefits of physical exercise (PE) act through or require a healthy, functional endothelium (beige cells). Items written in green are upregulated or improved by PE, while those written in red are decreased or downregulated. PE increases the bioavailability of NO, which is synthesized by eNOS in endothelial cells. PE improves quality and increases quantity of sleep, which can facilitate clearance of toxic protein aggregates including amyloid and hyperphosphorylated tau by the glymphatic system. This clearance prevents amyloid from activating astrocytes (green cell), and thus prevents proinflammatory mediators from entering blood vessels and damaging the endothelium. PE can increase LRP-1 and decrease RAGE found on endothelial cells. PE improves CBF, which can in turn decrease the amount of cerebral amyloid angiopathy (CAA) around vessels and thus improve endothelial cell health. PE can decrease TNF-α and IL-1 levels in the periphery, as well as intracellular adhesion molecule (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1), which could prevent the transcription of proinflammatory proteins and entry of leukocytes across the BBB. PE increases the activity of superoxide dismutase (SOD) enzymes and SIRT3 in mitochondria (peach cell), keeping ROS at low levels that will not negatively impact endothelial cell function. PE has been shown to upregulate GULT1 receptors found on endothelial cells, allowing more glucose into the brain. When glucose enters oligodendrocytes (orange cell) it is converted into lipids that are used to synthesize myelin. Another key component to myelin synthesis is lactate, which is upregulated by PE and enters the brain through MCT1 receptors found on endothelial cells. PE increases both brain derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) transcription in endothelial cells, as well as activation of the Wnt/β-catenin pathway, which synthesizes β-catenin that is part of the structure of tight junctions between endothelial cells. These mechanisms may be important for neurogenesis and angiogenesis. Akt: protein kinase B; PI3K: phosphatidylinositol 3-kinase; SIRT3: sirtuin 3; HIF-1α: hypoxia-inducible factor 1α; IL-1β: interleukin 1β; TNF-α: tumor necrosis factor alpha; COX-2: cycloxygenase 2.