Cholesterol, Atherosclerosis, and APOE in Vascular Contributions to Cognitive Impairment and Dementia (VCID): Potential Mechanisms and Therapy

Vascular contributions to cognitive impairment and dementia (VCID) are a common cause of cognitive decline, yet limited therapies exist. This cerebrovascular disease results in neurodegeneration via acute, chronic, local, and systemic mechanisms. The etiology of VCID is complex, with a significant i...

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Vydáno v:	Frontiers in aging neuroscience Ročník 13; s. 647990
Hlavní autoři:	Duong, Michael Tran, Nasrallah, Ilya M., Wolk, David A., Chang, Catherine C. Y., Chang, Ta-Yuan
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	Switzerland Frontiers Research Foundation 25.03.2021 Frontiers Media S.A
Témata:	Alzheimer's disease APOE Apolipoprotein E Apolipoprotein E4 Arteriosclerosis Astrocytes Atherosclerosis Blood flow Blood-brain barrier Carotid arteries Carotid artery Cell activation Cerebral blood flow Cerebrovascular diseases Cholesterol Clinical aspects Cognitive ability Dementia Dementia disorders Dyslipidemia Endothelial cells Etiology glia Homeostasis Hypercholesterolemia Inflammation Ischemia Lipids Metabolism Microglia Neurodegeneration Neurodegenerative diseases Neuroscience Pathology Proteins Risk factors Smooth muscle Stroke vascular dementia Veins & arteries atherosclerosis inflammation vascular dementia cholesterol macrophage APOE glia
ISSN:	1663-4365, 1663-4365
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Popis
Shrnutí:	Vascular contributions to cognitive impairment and dementia (VCID) are a common cause of cognitive decline, yet limited therapies exist. This cerebrovascular disease results in neurodegeneration via acute, chronic, local, and systemic mechanisms. The etiology of VCID is complex, with a significant impact from atherosclerosis. Risk factors including hypercholesterolemia and hypertension promote intracranial atherosclerotic disease and carotid artery stenosis (CAS), which disrupt cerebral blood flow and trigger ischemic strokes and VCID. Apolipoprotein E (APOE) is a cholesterol and phospholipid carrier present in plasma and various tissues. APOE is implicated in dyslipidemia and Alzheimer disease (AD); however, its connection with VCID is less understood. Few experimental models for VCID exist, so much of the present information has been drawn from clinical studies. Here, we review the literature with a focus on the clinical aspects of atherosclerotic cerebrovascular disease and build a working model for the pathogenesis of VCID. We describe potential intermediate steps in this model, linking cholesterol, atherosclerosis, and APOE with VCID. APOE4 is a minor isoform of APOE that promotes lipid dyshomeostasis in astrocytes and microglia, leading to chronic neuroinflammation. APOE4 disturbs lipid homeostasis in macrophages and smooth muscle cells, thus exacerbating systemic inflammation and promoting atherosclerotic plaque formation. Additionally, APOE4 may contribute to stromal activation of endothelial cells and pericytes that disturb the blood-brain barrier (BBB). These and other risk factors together lead to chronic inflammation, atherosclerosis, VCID, and neurodegeneration. Finally, we discuss potential cholesterol metabolism based approaches for future VCID treatment.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 Reviewed by: Takahisa Kanekiyo, Mayo Clinic Florida, United States; Stefano Tarantini, University of Oklahoma Health Sciences Center, United States Edited by: Irina A. Pikuleva, Case Western Reserve University, United States
ISSN:	1663-4365 1663-4365
DOI:	10.3389/fnagi.2021.647990