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The role of APOE in cerebrovascular dysfunction

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Abstract

The ε4 allele of the apolipoprotein E gene (APOE4) is associated with cognitive decline during aging, is the greatest genetic risk factor for Alzheimer’s disease and has links to other neurodegenerative conditions that affect cognition. Increasing evidence indicates that APOE genotypes differentially modulate the function of the cerebrovasculature (CV), with apoE and its receptors expressed by different cell types at the CV interface (astrocytes, pericytes, smooth muscle cells, brain endothelial cells). However, research on the role of apoE in CV dysfunction has not advanced as quickly as other apoE-modulated pathways. This review will assess what aspects of the CV are modulated by APOE genotypes during aging and under disease states, discuss potential mechanisms, and summarize the therapeutic significance of the topic. We propose that APOE4 induces CV dysfunction through direct signaling at the CV, and indirectly via modulation of peripheral and central pathways. Further, that APOE4 predisposes the CV to damage by, and exacerbates the effects of, additional risk factors (such as sex, hypertension, and diabetes). ApoE4-induced detrimental CV changes include reduced cerebral blood flow (CBF), modified neuron-CBF coupling, increased blood–brain barrier leakiness, cerebral amyloid angiopathy, hemorrhages and disrupted transport of nutrients and toxins. The apoE4-induced detrimental changes may be linked to pericyte migration/activation, astrocyte activation, smooth muscle cell damage, basement membrane degradation and alterations in brain endothelial cells.

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Abbreviations

Aβ:

Amyloid-β

AD:

Alzheimer’s disease

apoE:

Apolipoprotein E

APOE-TR:

APOE-targeted replacement mice

ASL:

Arterial spin labeling

BBB:

Blood–brain barrier

BEC:

Brain endothelial cells

CAA:

Cerebral amyloid angiopathy

CBF:

Cerebral blood flow

CSF:

Cerebrospinal spinal fluid

CNS:

Central nervous system

CV:

Cerebrovasculature

cypA:

Cyclophilin A

FAD:

Familial AD

ISF:

Interstitial fluid

KO:

Knockout

LDLR:

Low-density lipoprotein receptor

LRP1:

Low-density lipoprotein receptor-related protein 1

MCI:

Mild cognitive impairment

MMP:

Matrix metalloproteinase

MS:

Multiple sclerosis

NVU:

Neurovascular unit

oAβ:

Oligomeric Aβ

TJ:

Tight junction

TNFα:

Tumor necrosis factor α

VaD:

Vascular dementia

VLDLR:

Very LDL receptor

WMH:

White matter hyperintensities

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Acknowledgments

L. M. T. is supported by UIC start-up funds. G. B. is supported by National Institutes of Health Grants RF1AG051504, R01AG027924, R01AG035355, R01AG046205, P01AG030128, P01NS074969, and P50AG016574, and grants from the Alzheimer’s Association and Cure Alzheimer’s Fund. The authors would also like to acknowledge Dr. Scott Brady (UIC) for critical scientific discussions on the topic.

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  1. Department of Anatomy and Cell Biology, University of Illinois at Chicago, 808 S.Wood St., M/C 512, Chicago, IL, 60612, USA

    Leon M. Tai, Riya Thomas, Felecia M. Marottoli, Kevin P. Koster & Alan W. J. Morris

  2. Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA

    Takahisa Kanekiyo & Guojun Bu

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  1. Leon M. Tai
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Tai, L.M., Thomas, R., Marottoli, F.M. et al. The role of APOE in cerebrovascular dysfunction. Acta Neuropathol 131, 709–723 (2016). https://doi.org/10.1007/s00401-016-1547-z

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