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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Veröffentlicht in:Frontiers in aging neuroscience Jg. 13; S. 647990
Hauptverfasser: Duong, Michael Tran, Nasrallah, Ilya M., Wolk, David A., Chang, Catherine C. Y., Chang, Ta-Yuan
Format: Journal Article
Sprache:Englisch
Veröffentlicht: Switzerland Frontiers Research Foundation 25.03.2021
Frontiers Media S.A
Schlagworte:
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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Zusammenfassung: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.
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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