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Cellular and Molecular Neurobiology

, Volume 36, Issue 2, pp 155–165 | Cite as

Endothelial Dysfunction and Amyloid-β-Induced Neurovascular Alterations

  • Kenzo Koizumi
  • Gang Wang
  • Laibaik ParkEmail author
Review Paper

Abstract

Alzheimer’s disease (AD) and cerebrovascular diseases share common vascular risk factors that have disastrous effects on cerebrovascular regulation. Endothelial cells, lining inner walls of cerebral blood vessels, form a dynamic interface between the blood and the brain and are critical for the maintenance of neurovascular homeostasis. Accordingly, injury in endothelial cells is regarded as one of the earliest symptoms of impaired vasoregulatory mechanisms. Extracellular buildup of amyloid-β (Aβ) is a central pathogenic factor in AD. Aβ exerts potent detrimental effects on cerebral blood vessels and impairs endothelial structure and function. Recent evidence implicates vascular oxidative stress and activation of the non-selective cationic channel transient receptor potential melastatin (TRPM)-2 on endothelial cells in the mechanisms of Aβ-induced neurovascular dysfunction. Thus, Aβ triggers opening of TRPM2 channels in endothelial cells leading to intracellular Ca2+ overload and vasomotor dysfunction. The cerebrovascular dysfunction may contribute to AD pathogenesis by reducing the cerebral blood supply, leading to increased susceptibility to vascular insufficiency, and by promoting Aβ accumulation. The recent realization that vascular factors contribute to AD pathobiology suggests new targets for the prevention and treatment of this devastating disease.

Keywords

Alzheimer’s disease β-amyloid Cerebral blood flow Cerebral endothelial cells TRPM2 

Abbreviations

ACA

TRPM2 inhibitor

AD

Alzheimer’s disease

ADPR

ADP-ribose

2-APB

TRPM2 inhibitor

β-amyloid

APP

Amyloid precursor protein

BBB

Blood–brain barrier

CAA

Cerebral amyloid angiopathy

CBF

Cerebral blood flow

CD36

Cluster of differentiation 36

CNS

Central nervous system

CSF

Cerebrospinal fluid

DNA

Deoxyribonucleic acid

γH2AX

Phosphorylated histone H2AX

GTP

Guanosine triphosphate

Mfsd2a

Major facilitator superfamily domain containing 2a

NADPH

Nicotinamide adenine dinucleotide phosphate

NO

Nitric oxide

Nox

NADPH oxidase

PARG

Poly(ADP-ribose) glycohydrolase

PARP

Poly(ADP-ribose) polymerase

PICALM

Phosphatidylcholine-binding clathrin assembly protein

PJ34

PARP inhibitor

phox

Phagocytic oxidase

Rac

Ras-related C3 botulinum toxin substrate

RAGE

Receptor for advanced glycogen end-products

ROS

Reactive oxygen species

siRNA

Small interfering RNA

SLC2A1

Solute carrier family 2 (Facilitated Glucose Transporter), Member 1

SOD

Superoxide dismutase

TRPM2

Transient receptor potential melastatin 2

VEGF

Vascular endothelial growth factor

Notes

Acknowledgments

The authors thank Dr. Costantino Iadecola for critical reading of the manuscript. This work was supported by the National Institutes of Health Grant NS37853, and by the American Heart Association Grant 09SDG2060701. The generous support of the Feil Family Foundation is gratefully acknowledged.

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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  1. 1.Feil Family Brain and Mind Research InstituteWeill Cornell Medical CollegeNew YorkUSA

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