Cerebrovascular Effects of Apolipoprotein E: Implications for Alzheimer Disease

Zlokovic, Berislav V.

doi:10.1001/jamaneurol.2013.2152

Cited by 263Barrier Structure and Function StudiesAlzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration Mechanisms

Cerebrovascular Effects of Apolipoprotein E: Implications for Alzheimer Disease

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Zlokovic, Berislav V.·2013·JAMA Neurology

DOI 10.1001/jamaneurol.2013.2152PMC PMC4414030

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Abstract

Human apolipoprotein E (apoE) has 3 isoforms: apoE2, apoE3, and apoE4. APOE4 is a major genetic risk factor for Alzheimer disease and is associated with dementia in Down syndrome and poor neurological outcome after traumatic brain injury, cerebral hemorrhage, and other neuropathological disorders. While apoE4 can induce neuropathology by participating in various cellular and molecular pathways, herein I review data supporting the hypothesis that apoE4 has direct toxic effects on the cerebrovascular system that in turn can lead to secondary neuronal dysfunction and degeneration as well as accumulation of neurotoxins in brain such as β-amyloid (Aβ) in Alzheimer disease. I review Aβ-independent cerebrovascular effects of apoE, particularly activation of a proinflammatory cyclophilin A-mediated pathway in brain vascular pericytes by apoE4 that has recently been shown to lead to a loss of cerebrovascular integrity and blood-brain barrier breakdown causing neuronal injury. I also review Aβ-dependent cerebrovascular effects of apoE such as faulty Aβ clearance from brain to circulation by apoE4. Finally, I discuss isoform-specific interactions of apoE with low-density lipoprotein receptor-related protein 1 on brain vascular cells (ie, endothelial cells, pericytes), which play an important role in Aβ-independent and Aβ-dependent effects of apoE on cerebral vasculature.

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APOE4 leads to BBB breakdown, vascular pathology, and diminished clearance of Aβ across the BBB.
“APOE4 leads to BBB breakdown, vascular pathology, and diminished clearance of A 𝛃 across the BBB (694), as discussed below.”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [694]
APOE exerts toxic effects on the cerebrovascular system and neurons and influences Aβ clearance, amyloid deposition, and tau-related neurodegeneration in an allele-dependent manner APOE4 > APOE3 > APOE2.
“APOE exerts toxic effects on the cerebrovascular system (694) and neurons (383, 384) and influences A 𝛃 clearance (60, 64, 98, 135, 256, 266, 278, 294, 315, 693), amyloid deposition (39, 256, 258, 266, 278, 314, 518, 612), and tau-related neurodegeneration (533) in an allele-dependent manner APOE4 > APOE3 > APOE2 .”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [694]

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Authors: Zlokovic, B. V.
Venue: JAMA Neurology
Publisher: American Medical Association (AMA)
Published: 2013-04-01
Volume: 70
Issue: 4
Pages: 440
ISSN: 2168-6149 (ISSN-L)
DOI: 10.1001/jamaneurol.2013.2152
PMC: PMC4414030
OpenAlex: W1994259160
Cited by: 263
References: 19
Citations by year: 2026: 9 · 2025: 15 · 2024: 13 · 2023: 15 · 2022: 17 · 2021: 21 · 2020: 14 · 2019: 17 · 2018: 17 · 2017: 23 · 2016: 24 · 2015: 30 · 2014: 42 · 2013: 5
FWCI: 18.90
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: JAMA Neurology (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: National Institutes of Health (NS34467)
National Institute on Aging (R01AG023084, R01AG039452, AG23084, R37AG023084, AG039452, RF1AG039452)
National Institute of Neurological Disorders and Stroke (R37NS034467, NS34467, R01NS034467)
Topics: Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords: apolipoprotein E, APOE ε4, APOE isoforms, cerebrovascular dysfunction, Alzheimer's disease, amyloid-beta, blood-brain barrier disruption, cyclophilin A, vascular pericytes, neuroinflammation, amyloid clearance, LDL receptor-related protein 1, cerebral vasculature, Down syndrome, traumatic brain injury, cerebral hemorrhage
MeSH terms: Alzheimer Disease, Animals, Apolipoproteins E, Blood-Brain Barrier, Cerebrovascular Circulation, Humans, Amyloid beta-Peptides, NF-kappa B, Matrix Metalloproteinase 9, Cyclophilin A

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Cerebrovascular Effects of Apolipoprotein E: Implications for Alzheimer Disease

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