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Neurovascular regulation in the normal brain and in Alzheimer's disease

Key Points

  • The rate of cerebral blood flow (CBF) is positively correlated with brain activity. This 'functional hyperaemia' is mediated by the coordinated action of various vasoactive agents — including ions that are associated with synaptic transmission and some neurotransmitters — on blood vessels.

  • The increases in CBF that are associated with neural activity are spatially restricted to the site of activity. Local interneurons and astrocytes are probably crucial to regulation of CBF at this level, producing and releasing vasoactive mediators.

  • Vasodilation of extracerebral arteries that supply the site of neural activity is probably achieved through the upstream transmission of vasoactive signals within the walls of blood vessels.

  • The 'neurovascular unit' — a functional entity comprising neurons, astrocytes, smooth muscle cells and endothelial cells — has a key role in the haemodynamic response to brain activity.

  • Disruption of this regulatory network occurs in response to brain injury; for example, during stroke. Evidence now indicates that cerebrovascular dysfunction is a feature of neurodegenerative disorders such as Alzheimer's disease.

  • Accumulation of amyloid β-peptide (Aβ) in brain is associated with neuronal death in Alzheimer's disease. Aβ induces dysfunction in all cell types of the neurovascular unit and interferes with the function of blood vessels. These effects are mediated through reactive oxygen species.

Abstract

The structural and functional integrity of the brain depends on the delicate balance between substrate delivery through blood flow and energy demands imposed by neural activity. Complex cerebrovascular control mechanisms ensure that active brain regions receive an adequate amount of blood, but the nature of these mechanisms remains elusive. Recent findings implicate perivascular neurons, gliovascular interactions and intramural vascular signalling in the control of the cerebral microcirculation. Neurons, astrocytes and vascular cells seem to constitute a functional unit, the primary purpose of which is to maintain the homeostasis of the brain's microenvironment. Alterations of these vascular regulatory mechanisms lead to brain dysfunction and disease. The emerging view is that cerebrovascular dysregulation is a feature not only of cerebrovascular pathologies, such as stroke, but also of neurodegenerative conditions, such as Alzheimer's disease.

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Figure 1: The ionic currents that are produced by axon potentials and synaptic processing generate extracellular field potentials.
Figure 2: Evoked neural events that underlie the increase in cerebral blood flow (CBF).
Figure 3: Vasoactive mediators released from neurons and glia by neural activity.
Figure 4: Local and propagated microvascular responses following activation of the somatosensory cortex.
Figure 5: Putative cellular mechanisms for the propagation of vasodilation from vessels in the activated site (arterioles and capillaries) to resistance arteries upstream (pial arteries).
Figure 6: Representative sources and targets of vascular reactive oxygen species (ROS).
Figure 7: Hypothetical time-course of the interplay between vascular dysregulation, neuropathological alterations (plaques, neurofibrillary tangles, synaptic loss) and decline in brain function in Alzheimer's disease.
Figure 8: Potential interactions between vascular factors (oligaemia) and amyloid β-peptide (Aβ) in the regulation of brain dysfunction in early (left) and late (right) Alzheimer's disease.

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Acknowledgements

Supported by grants from the National Institutes of Health. The author is the recipient of a Javits award from the National Institute of Neurological Disorders and Stroke. J. Victor and V. Pickel provided helpful comments. The work of many colleagues could not be cited because of space limitations.

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Glossary

CYCLOOXYGENASE

Rate-limiting enzyme for the synthesis of prostanoids from arachidonic acid.

P450 EPOXYGENASE

Family of enzymes that synthesizes epoxyeicosatrienoic acids and hydroxyeicosatrienoic acids from arachidonic acid.

CYCLIN D2

An enzyme that controls the cell cycle by activating cyclin-dependent kinases leading to phosphorylation of cell cycle regulatory proteins.

STELLATE INTERNEURONS

Inhibitory interneurons located in the outer layer of the cerebellar cortex, or molecular layer.

PROSTANOIDS

Cyclooxygenase reaction products including prostaglandins and thromboxanes.

SWEDISH MUTATION

Abnormality in the amyloid precursor protein gene that was discovered in a Swedish family that has an unusually high incidence of early-onset Alzheimer's disease.

SCAVENGER RECEPTOR

Membrane glycoprotein that mediates the recognition and uptake of various negatively charged macromolecules.

NORLEUCINE

An unnatural amino acid that is used experimentally to study protein structure and function.

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Iadecola, C. Neurovascular regulation in the normal brain and in Alzheimer's disease. Nat Rev Neurosci 5, 347–360 (2004). https://doi.org/10.1038/nrn1387

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