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Acta Neuropathologica

, Volume 131, Issue 5, pp 709–723 | Cite as

The role of APOE in cerebrovascular dysfunction

  • Leon M. TaiEmail author
  • Riya Thomas
  • Felecia M. Marottoli
  • Kevin P. Koster
  • Takahisa Kanekiyo
  • Alan W. J. Morris
  • Guojun Bu
Review

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.

Keywords

Aging Alzheimer’s disease Apolipoprotein E Blood–brain barrier Cerebrovascular dysfunction 

Abbreviations

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

Notes

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.

Supplementary material

401_2016_1547_MOESM1_ESM.docx (133 kb)
Supplementary material 1 (DOCX 134 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Leon M. Tai
    • 1
    Email author
  • Riya Thomas
    • 1
  • Felecia M. Marottoli
    • 1
  • Kevin P. Koster
    • 1
  • Takahisa Kanekiyo
    • 2
  • Alan W. J. Morris
    • 1
  • Guojun Bu
    • 2
  1. 1.Department of Anatomy and Cell BiologyUniversity of Illinois at ChicagoChicagoUSA
  2. 2.Department of NeuroscienceMayo ClinicJacksonvilleUSA

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