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.
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Abbreviations
- ACA:
-
TRPM2 inhibitor
- AD:
-
Alzheimer’s disease
- ADPR:
-
ADP-ribose
- 2-APB:
-
TRPM2 inhibitor
- Aβ:
-
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
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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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Koizumi, K., Wang, G. & Park, L. Endothelial Dysfunction and Amyloid-β-Induced Neurovascular Alterations. Cell Mol Neurobiol 36, 155–165 (2016). https://doi.org/10.1007/s10571-015-0256-9
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DOI: https://doi.org/10.1007/s10571-015-0256-9