Vascular contributions to cognitive impairment and dementia: the emerging role of 20-HETE

Abstract

The accumulation of extracellular amyloid-β (Aβ) and intracellular hyperphosphorylated τ proteins in the brain are the hallmarks of Alzheimer’s disease (AD). Much of the research into the pathogenesis of AD has focused on the amyloid or τ hypothesis. These hypotheses propose that Aβ or τ aggregation is the inciting event in AD that leads to downstream neurodegeneration, inflammation, brain atrophy and cognitive impairment. Multiple drugs have been developed and are effective in preventing the accumulation and/or clearing of Aβ or τ proteins. However, clinical trials examining these therapeutic agents have failed to show efficacy in preventing or slowing the progression of the disease. Thus, there is a need for fresh perspectives and the evaluation of alternative therapeutic targets in this field. Epidemiology studies have revealed significant overlap between cardiovascular and cerebrovascular risk factors such as hypertension, diabetes, atherosclerosis and stroke to the development of cognitive impairment. This strong correlation has given birth to a renewed focus on vascular contributions to AD and related dementias. However, few genes and mechanisms have been identified. 20-Hydroxyeicosatetraenoic acid (20-HETE) is a potent vasoconstrictor that plays a complex role in hypertension, autoregulation of cerebral blood flow and blood–brain barrier (BBB) integrity. Multiple human genome-wide association studies have linked mutations in the cytochrome P450 (CYP) 4A (CYP4A) genes that produce 20-HETE to hypertension and stroke. Most recently, genetic variants in the enzymes that produce 20-HETE have also been linked to AD in human population studies. This review examines the emerging role of 20-HETE in AD and related dementias.

Impact of impaired cerebral blood flow autoregulation on cognitive impairment

“…20-HETE is a potent vasoconstrictor affecting cerebrovascular MR and CBF autoregulation by inhibiting BK ca channels and activating L-type Ca 2+ channels, which causes depolarization of VSMCs to induce vasoconstriction (Harder et al, 2011;Roman and Fan, 2018). The reduction in 20-HETE results in impaired cerebrovascular MR and CBF autoregulation, contributing to BBB leakage elevations in blood pressure in Dahl Salt-Sensitive (Dahl S) rats (Fan et al, 2015;Shekhar et al, 2017a;Gonzalez-Fernandez et al, 2021). Similarly, a decrease in 20-HETE production with aging contributes to the loss of CBF autoregulation in angiotensin II (Ang II)-induced hypertensive mice (Toth et al, 2015).…”

Research trends and hotspots of post-stroke cognitive impairment: a bibliometric analysis

“…Research has found that approximately one-third of patients with VaD may have coincidental AD pathology ( Gorelick and Nyenhuis, 2013 ) and that amyloid plaques and neurofibrillary tangles are more likely to cause AD if accompanied by vascular risk ( Rabin et al, 2018 ). Moreover, plasma osteopontin, brain angiotensin type 2 receptors, and 20-hydroxyeicosatetraenoic acid have been confirmed as the common potential targets and biomarkers of AD and VCI ( Ahmed and Ishrat, 2020 ; Chai et al, 2021 ; Gonzalez-Fernandez et al, 2021 ).…”

“…Research has found that approximately onethird of patients with VaD may have coincidental AD pathology Frontiers in Pharmacology frontiersin.org (Gorelick and Nyenhuis, 2013) and that amyloid plaques and neurofibrillary tangles are more likely to cause AD if accompanied by vascular risk (Rabin et al, 2018). Moreover, plasma osteopontin, brain angiotensin type 2 receptors, and 20hydroxyeicosatetraenoic acid have been confirmed as the common potential targets and biomarkers of AD and VCI (Ahmed and Ishrat, 2020;Chai et al, 2021;Gonzalez-Fernandez et al, 2021). PSCI, a type of VCI, is a major complication of stroke that mediates a range of syndromes, from mild cognitive impairment to dementia, with emphasis on stroke events triggering cognitive dysfunction (Zhang and Bi, 2020).…”

Turn Up the HETE on Septic Shock

“…20,21 The present study by Tunctan et al 1 investigated whether the activation of GPR75-mediated signaling in various vascular beds is responsible for the ability of 5,14-HEDGE to prevent vascular hyporeactivity, hypotension, and tachycardia in the LPS-induced rat model of septic shock. Recent studies have shown that GPR75 is highly expressed in the brain, cerebral arterioles, and pericytes, 23,24 but very little is currently known about its expression in the aorta and other vessels throughout the rest of the body. 1,21 Moreover, studies have yet to demonstrate whether the effects of 20-HETE on K Ca channel activity or vascular tone are mediated by its effects on the GPR75 receptor.…”