Cerebral blood flow regulation and neurovascular dysfunction in Alzheimer disease

Nature Reviews Neuroscience volume 18, pages419–434(2017)Cite this article

Subjects

Key Points

  • Here, we review literature determining the arterial and arteriolar component of cerebral blood flow regulation.

  • Furthermore, we describe evidence of arterial and arteriolar blood flow control by vascular smooth muscle cells (VSMCs), astrocyte-mediated, direct neuron-mediated and endothelium-mediated regulation of VSMC tone.

  • Also, we discuss the capillary component of cerebral blood flow regulation.

  • Importantly, we highlight recent findings regarding the control of capillary blood flow by pericytes, and signalling in astrocytes and pericytes regulating capillary tone.

  • In addition, we examine vascular dysfunction in animal models, including amyloid-β-independent vascular changes, amyloid-β-dependent vascular changes and combined amyloid-β and vascular models.

  • Last, we emphasize Alzheimer disease vascular dysfunction, including cerebrovascular reactivity, cerebral blood flow reductions and neurovascular uncoupling.

Abstract

Cerebral blood flow (CBF) regulation is essential for normal brain function. The mammalian brain has evolved a unique mechanism for CBF control known as neurovascular coupling. This mechanism ensures a rapid increase in the rate of CBF and oxygen delivery to activated brain structures. The neurovascular unit is composed of astrocytes, mural vascular smooth muscle cells and pericytes, and endothelia, and regulates neurovascular coupling. This Review article examines the cellular and molecular mechanisms within the neurovascular unit that contribute to CBF control, and neurovascular dysfunction in neurodegenerative disorders such as Alzheimer disease.

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Figure 1: A schematic representation of the neurovascular unit showing cellular elements regulating cerebral blood flow along the vascular tree.
Figure 2: Arteriolar regulation of cerebral blood flow.
Figure 3: Capillary regulation of cerebral blood flow.
Figure 4: Neurovascular dysfunction in Alzheimer disease: two-hit vascular hypothesis.

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Acknowledgements

The work of B.V.Z. is supported by the US National Institutes of Health (grants R01AG023084, R01NS090904, R01NS034467, R01AG039452, R01NS100459, P01AG052350) and Cure for Alzheimer's fund. The authors thank M. Sweeney for careful reading of the manuscript.

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  1. Kassandra Kisler, Amy R. Nelson and Axel Montagne: These authors contributed equally to this work.

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  1. Zilkha Neurogenetic Institute, 1501 San Pablo Street, Los Angeles, 90089, California, USA
    • Kassandra Kisler
    • , Amy R. Nelson
    • , Axel Montagne
    •  & Berislav V. Zlokovic
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Glossary

Neurovascular coupling

The dynamic functional change in cerebral blood flow that occurs in response to local neuronal activity.

Functional hyperaemia

The increase in cerebral blood flow that occurs in response to brain activity.

Neurovascular unit

(NVU). A functionally integrated group of different cell types in the brain composed of vascular cells (endothelial cells, vascular smooth muscle cells and pericytes), glia (astrocytes, microglia and oligodendrocytes) and neurons.

Functional connectivity

The temporal dependency of neuronal activation patterns of anatomically separated brain regions determined by measuring the level of co-activation of resting-state MRI time series between brain regions.

Cytochrome P450

Enzymes belonging to a superfamily of haemoproteins that contain haem as a cofactor.

Cyclooxygenase 1

(COX1). An enzyme, also known as prostaglandin-endoperoxide synthase 1, responsible for the formation of prostanoids and prostaglandins.

Mechanical shear stress

The physical stress caused to endothelial cells by the flow of blood through vessels.

Hypercapnia

A condition of abnormally increased carbon dioxide levels in the blood.

Vasculotropic

Affecting, acting upon or attracted to blood vessels

Microhaemorrhages

Small focal cerebral microbleeds in the brain, which can be visualized by MRI sequences.

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Kisler, K., Nelson, A., Montagne, A. et al. Cerebral blood flow regulation and neurovascular dysfunction in Alzheimer disease. Nat Rev Neurosci 18, 419–434 (2017). https://doi.org/10.1038/nrn.2017.48

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