Intermittent hypoxia training protects cerebrovascular function in Alzheimer's disease

Abstract

Alzheimer's disease (AD) is a leading cause of death and disability among older adults. Modifiable vascular risk factors for AD (VRF) include obesity, hypertension, type 2 diabetes mellitus, sleep apnea, and metabolic syndrome. Here, interactions between cerebrovascular function and development of AD are reviewed, as are interventions to improve cerebral blood flow and reduce VRF. Atherosclerosis and small vessel cerebral disease impair metabolic regulation of cerebral blood flow and, along with microvascular rarefaction and altered trans-capillary exchange, create conditions favoring AD development. Although currently there are no definitive therapies for treatment or prevention of AD, reduction of VRFs lowers the risk for cognitive decline. There is increasing evidence that brief repeated exposures to moderate hypoxia, i.e. intermittent hypoxic training (IHT), improve cerebral vascular function and reduce VRFs including systemic hypertension, cardiac arrhythmias, and mental stress. In experimental AD, IHT nearly prevented endothelial dysfunction of both cerebral and extra-cerebral blood vessels, rarefaction of the brain vascular network, and the loss of neurons in the brain cortex. Associated with these vasoprotective effects, IHT improved memory and lessened AD pathology. IHT increases endothelial production of nitric oxide (NO), thereby increasing regional cerebral blood flow and augmenting the vaso- and neuroprotective effects of endothelial NO. On the other hand, in AD excessive production of NO in microglia, astrocytes, and cortical neurons generates neurotoxic peroxynitrite. IHT enhances storage of excessive NO in the form of S-nitrosothiols and dinitrosyl iron complexes. Oxidative stress plays a pivotal role in the pathogenesis of AD, and IHT reduces oxidative stress in a number of experimental pathologies. Beneficial effects of IHT in experimental neuropathologies other than AD, including dyscirculatory encephalopathy, ischemic stroke injury, audiogenic epilepsy, spinal cord injury, and alcohol withdrawal stress have also been reported. Further research on the potential benefits of IHT in AD and other brain pathologies is warranted.

Keywords: Alzheimer's disease; brain ischemia; cerebral circulation; cerebrovascular risk factors; cognitive function; intermittent hypoxia training; neurodegeneration; nitric oxide; nitrosative stress; oxidative stress; vasoprotection.

© 2016 by the Society for Experimental Biology and Medicine.

Figures

Figure 1

Alzheimer's Disease (AD) risk factors. Risk factors for AD are grouped into those that cannot be modified, i.e. are fixed (upper left) and those that are modifiable by intermittent hypoxia training (IHT) and potentially other interventions (upper right). These fixed and modifiable risk factors give rise to the injury mediators amyloid β, inflammation, reactive oxygen and nitrogen species (RONS), and suppression of endothelial nitric oxide synthase (eNOS) which, in turn, damage macro- and microvascular components of the cerebral circulation. The resultant impairment of cerebral blood supply causes neurodegeneration which culminates in neurocognitive impairment

Figure 2

The vicious cycle of dementation and cerebral underperfusion. Decreased activity lowers energy consumption and, thus, demand for blood flow in that brain region. On the other hand, impaired local blood flow, e.g. due to cerebrovascular disease, compromises oxygen and fuel delivery and, thus, ATP production to support brain function. Severe and/or prolonged underperfusion causes neurodegeneration by the mechanisms diagramed in Figure 1. Lower right: the broken lines designate mechanisms mobilized by intermittent hypoxia training (IHT) to acutely increase metabolic vasodilation via nitric oxide (NO) formation, and the more sustained adaptive increase in microvascular density via hypoxia-inducible factor (HIF) induction of vascular endothelial growth factor (VEGF), the principal activator of angiogenesis