The Neurovascular Unit Coming of Age: A Journey through Neurovascular Coupling in Health and Disease

Neuron, Journal Year: 2017, Volume and Issue: 96(1), P. 17 - 42

Published: Sept. 1, 2017

Language: Английский

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Amyloid β oligomers constrict human capillaries in Alzheimer’s disease via signaling to pericytes

Science, Journal Year: 2019, Volume and Issue: 365(6450)

Published: June 20, 2019

Cerebral blood flow is reduced early in the onset of Alzheimer's disease (AD). Because most vascular resistance within brain capillaries, this could reflect dysfunction contractile pericytes on capillary walls. We used live and rapidly fixed biopsied human tissue to establish relevance, rodent experiments define mechanism. found that humans with cognitive decline, amyloid β (Aβ) constricts capillaries at pericyte locations. This was caused by Aβ generating reactive oxygen species, which evoked release endothelin-1 (ET) activated ETA receptors. Capillary, but not arteriole, constriction also occurred vivo a mouse model AD. Thus, inhibiting potentially reduce energy lack neurodegeneration

Language: Английский

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Revisiting the neurovascular unit

Nature Neuroscience, Journal Year: 2021, Volume and Issue: 24(9), P. 1198 - 1209

Published: Aug. 5, 2021

Language: Английский

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Brain capillary pericytes exert a substantial but slow influence on blood flow

Nature Neuroscience, Journal Year: 2021, Volume and Issue: 24(5), P. 633 - 645

Published: Feb. 18, 2021

Language: Английский

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Cerebral blood flow decrease as an early pathological mechanism in Alzheimer's disease

Acta Neuropathologica, Journal Year: 2020, Volume and Issue: 140(6), P. 793 - 810

Published: Aug. 31, 2020

Abstract Therapies targeting late events in Alzheimer’s disease (AD), including aggregation of amyloid beta (Aβ) and hyperphosphorylated tau, have largely failed, probably because they are given after significant neuronal damage has occurred. Biomarkers suggest that the earliest event AD is a decrease cerebral blood flow (CBF). This caused by constriction capillaries contractile pericytes, evoked oligomeric Aβ. CBF also reduced neutrophil trapping clot formation, perhaps secondary to capillary constriction. The fall potentiates neurodegeneration upregulating BACE1 enzyme makes Aβ promoting tau hyperphosphorylation. Surprisingly, therefore, reduction may play crucial role driving cognitive decline initiating cascade itself, or being amplifying production. Here, we review developments this area neglected current approaches AD, with aim novel mechanism-based therapeutic approaches.

Language: Английский

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Targeting pericytes for therapeutic approaches to neurological disorders

Acta Neuropathologica, Journal Year: 2018, Volume and Issue: 136(4), P. 507 - 523

Published: Aug. 10, 2018

Many central nervous system diseases currently lack effective treatment and are often associated with defects in microvascular function, including a failure to match the energy supplied by blood used on neuronal computation, or breakdown of blood–brain barrier. Pericytes, an under-studied cell type located capillaries, crucial importance regulating diverse functions, such as angiogenesis, barrier, capillary flow movement immune cells into brain. They also form part "glial" scar isolating damaged parts CNS, may have stem cell-like properties. Recent studies suggested that pericytes play role neurological diseases, thus therapeutic target disorders stroke, traumatic brain injury, migraine, epilepsy, spinal cord diabetes, Huntington's disease, Alzheimer's multiple sclerosis, glioma, radiation necrosis amyotrophic lateral sclerosis. Here we report recent advances our understanding pericyte biology discuss how could be targeted develop novel approaches disorders, increasing flow, preserving barrier entry modulating formation vessels in, glial around, regions.

Language: Английский

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Brain Microvascular Pericytes in Vascular Cognitive Impairment and Dementia

Frontiers in Aging Neuroscience, Journal Year: 2020, Volume and Issue: 12

Published: April 14, 2020

Pericytes are unique, multi-functional mural cells localized at the abluminal side of perivascular space in microvessels. Originally discovered nineteenth century, pericytes had drawn less attention until decades ago mainly due to lack specific markers. Recently, however, a growing body evidence has revealed that play various important roles: development and maintenance blood-brain barrier (BBB), regulation neurovascular system (e.g., vascular stability, vessel formation, cerebral blood flow, etc.), trafficking inflammatory cells, clearance toxic waste products from brain, acquisition stem cell-like properties. In unit, perform these functions through coordinated crosstalk with neighboring including endothelial, glial, neuronal cells. Dysfunction contribute wide variety diseases lead cognitive impairments such as small disease (SVD), acute stroke, Alzheimer’s (AD), other neurological disorders. For instance, SVDs, pericyte degeneration leads microvessel instability demyelination while constriction after ischemia causes no-reflow phenomenon brain capillaries. AD, which shares some common risk factors dementia, reduction coverage subsequent microvascular observed association white matter attenuation impaired cognition. Pericyte loss BBB-breakdown, stagnates amyloid β leakage neurotoxic molecules into parenchyma. this review, we first summarize characteristics pericytes, their roles central nervous system. Then, focus on how dysfunctional pathogenesis impairment ‘small vessel’ ‘large diseases, well AD. Finally, discuss therapeutic implications for disorders by targeting pericytes.

Language: Английский

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Neurovascular coupling and oxygenation are decreased in hippocampus compared to neocortex because of microvascular differences

Nature Communications, Journal Year: 2021, Volume and Issue: 12(1)

Published: May 27, 2021

Abstract The hippocampus is essential for spatial and episodic memory but damaged early in Alzheimer’s disease very sensitive to hypoxia. Understanding how it regulates its oxygen supply therefore key designing interventions preserve function. However, studies of neurovascular function the vivo have been limited by relative inaccessibility. Here we compared hippocampal visual cortical awake mice, using two photon imaging individual neurons vessels measures regional blood flow haemoglobin oxygenation. We show that flow, oxygenation coupling were decreased neocortex, because differences both vascular network pericyte endothelial cell Modelling diffusion indicates these features vasculature may restrict availability could explain sensitivity damage during neurological conditions, including disease, where brain’s energy decreased.

Language: Английский

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The Ca2+-gated channel TMEM16A amplifies capillary pericyte contraction and reduces cerebral blood flow after ischemia

Journal of Clinical Investigation, Journal Year: 2022, Volume and Issue: 132(9)

Published: March 22, 2022

Pericyte-mediated capillary constriction decreases cerebral blood flow in stroke after an occluded artery is unblocked. The determinants of pericyte tone are poorly understood. We show that a small rise cytoplasmic Ca2+ concentration ([Ca2+]i) pericytes activated chloride efflux through the Ca2+-gated anion channel TMEM16A, thus depolarizing cell and opening voltage-gated calcium channels. This mechanism strongly amplified [Ca2+]i evoked by contractile agonists ischemia. In rodent model, TMEM16A inhibition slowed ischemia-evoked rise, constriction, death; reduced neutrophil stalling; improved cerebrovascular reperfusion. Genetic analysis implicated altered expression poor patient recovery from ischemic stroke. Thus, crucial regulator function potential therapeutic target for possibly other disorders impaired microvascular flow, such as Alzheimer's disease vascular dementia.

Language: Английский

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Neurovascular coupling mechanisms in health and neurovascular uncoupling in Alzheimer’s disease

Brain, Journal Year: 2022, Volume and Issue: 145(7), P. 2276 - 2292

Published: May 13, 2022

Abstract To match the metabolic demands of brain, mechanisms have evolved to couple neuronal activity vasodilation, thus increasing local cerebral blood flow and delivery oxygen glucose active neurons. Rather than relying on feedback signals such as consumption or glucose, main signalling pathways rely release vasoactive molecules by neurons astrocytes, which act contractile cells. Vascular smooth muscle cells pericytes are associated with arterioles capillaries, respectively, relax induce vasodilation. Much progress has been made in understanding complex neurovascular coupling, but issues contributions capillary astrocyte calcium signal remain contentious. Study coupling is especially important dysregulation a prominent feature Alzheimer’s disease. In this article we will discuss developments controversies finish discussing current knowledge concerning uncoupling

Language: Английский

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