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Cited by 191Neurological Disease Mechanisms and TreatmentsBarrier Structure and Function StudiesTraumatic Brain Injury and Neurovascular Disturbances

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Neurovascular Dysfunction in Vascular Dementia, Alzheimer's and Atherosclerosis

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Shabir, Osman, Berwick, Jason, Francis, Sheila E.·2018·BMC Neuroscience
DOI 10.1186/s12868-018-0465-5PMC PMC6192291
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Abstract

Efficient blood supply to the brain is of paramount importance to its normal functioning and improper blood flow can result in potentially devastating neurological consequences. Cerebral blood flow in response to neural activity is intrinsically regulated by a complex interplay between various cell types within the brain in a relationship termed neurovascular coupling. The breakdown of neurovascular coupling is evident across a wide variety of both neurological and psychiatric disorders including Alzheimer's disease. Atherosclerosis is a chronic syndrome affecting the integrity and function of major blood vessels including those that supply the brain, and it is therefore hypothesised that atherosclerosis impairs cerebral blood flow and neurovascular coupling leading to cerebrovascular dysfunction. This review will discuss the mechanisms of neurovascular coupling in health and disease and how atherosclerosis can potentially cause cerebrovascular dysfunction that may lead to cognitive decline as well as stroke. Understanding the mechanisms of neurovascular coupling in health and disease may enable us to develop potential therapies to prevent the breakdown of neurovascular coupling in the treatment of vascular brain diseases including vascular dementia, Alzheimer's disease and stroke.

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Figures

Fig. 1 The neurovascular unit and the BBB at a capillary. Cerebral arteries have extensive vascular smooth muscle cell (VSMC) coverage regulating vasoconstriction. Capillaries on the other hand lack vascular smooth muscle cells, and are instead covered by small pericytes which maintain the integrity of the BBB, as well as regulate their diameter. Cerebral vessels receive inputs from astrocytes by their end-feet to regulate arteriolar diameter, as well as inputs from various interneuron groups
Fig. 1 The neurovascular unit and the BBB at a capillary. Cerebral arteries have extensive vascular smooth muscle cell (VSMC) coverage regulating vasoconstriction. Capillaries on the other hand lack vascular smooth muscle cells, and are instead covered by small pericytes which maintain the integrity of the BBB, as well as regulate their diameter. Cerebral vessels receive inputs from astrocytes by their end-feet to regulate arteriolar diameter, as well as inputs from various interneuron groupsCC BY · PubMed Central
Fig. 2 Neurophysiology of neurovascular coupling overview. Neural activity is metabolically expensive demanding a high consumption of glucose and oxygen (from arterial blood). Simultaneously, CO2 and other by products are also produced, which need to be removed by diffusion into venous blood in order to prevent hypercapnia and acidosis. In order to achieve this, neurons regulate blood flow via neurovascular coupling. Vasoactive agents such as NO directly cause vasodilation of arterial smooth muscle cells. Significant neurogliovascular signalling involving glutamate and calcium signalling causes vasodilation via channels on VSMCs e.g. BKCa, TRPV4, to stimulate cGMP [105]. There are indeed multiple and complex signalling pathways (including ATP and VIP signalling) also involved in neurovascular coupling. In addition to vasodilator signals, vasoconstrictive signals are also produced, namely 20-HETE, however this is thought to be pathological and as a result of ageing [106]. Pericytes regulate capillary diameter by responding to glutamate release, in addition to PGE2 produced by astrocytes
Fig. 2 Neurophysiology of neurovascular coupling overview. Neural activity is metabolically expensive demanding a high consumption of glucose and oxygen (from arterial blood). Simultaneously, CO2 and other by products are also produced, which need to be removed by diffusion into venous blood in order to prevent hypercapnia and acidosis. In order to achieve this, neurons regulate blood flow via neurovascular coupling. Vasoactive agents such as NO directly cause vasodilation of arterial smooth muscle cells. Significant neurogliovascular signalling involving glutamate and calcium signalling causes vasodilation via channels on VSMCs e.g. BKCa, TRPV4, to stimulate cGMP [105]. There are indeed multiple and complex signalling pathways (including ATP and VIP signalling) also involved in neurovascular coupling. In addition to vasodilator signals, vasoconstrictive signals are also produced, namely 20-HETE, however this is thought to be pathological and as a result of ageing [106]. Pericytes regulate capillary diameter by responding to glutamate release, in addition to PGE2 produced by astrocytesCC BY · PubMed Central
Fig. 3 Overview of Aβ processing. APP can be processed via the α-secretase pathways (non-amyloidgenic pathway) producing the soluble APPs-α fragment and a small p3 fragment. The amyloidgenic pathway utilises β-secretase to produce the soluble APPs-β fragment followed by γ-secretase producing Aβ40 or lower in a much higher ratio than the production of Aβ42. Mutations to PSEN1/2 and APP (such as the Swedish mutation, marked by a red star on APP) often favour the production of the more toxic Aβ42 fragment which forms oligomers leading to the formation of Aβ-plaques. Adapted from [51, 70]
Fig. 3 Overview of Aβ processing. APP can be processed via the α-secretase pathways (non-amyloidgenic pathway) producing the soluble APPs-α fragment and a small p3 fragment. The amyloidgenic pathway utilises β-secretase to produce the soluble APPs-β fragment followed by γ-secretase producing Aβ40 or lower in a much higher ratio than the production of Aβ42. Mutations to PSEN1/2 and APP (such as the Swedish mutation, marked by a red star on APP) often favour the production of the more toxic Aβ42 fragment which forms oligomers leading to the formation of Aβ-plaques. Adapted from [51, 70]CC BY · PubMed Central
Fig. 4 Overview of the pathogenesis of atherosclerosis. Accumulation of LDLs in the blood leads to LDLs being transported into the endothelium, where they become oxidised. Infiltrating monocytes become activated and differentiate into macrophages and begin to ingest oxidised-LDLs to become foam cells. Over time, foam cells conglomerate to form fatty streaks. Simultaneously, due to inflammation and stimulant factors, VSMCs begin to proliferate and migrate into the intima and form a cap around the fatty streak. Endothelial cells overlying the growing plaque become calcified, with reduced elasticity. Over time this cap restricts blood flow due to a luminal constriction. If the plaque ruptures, a thrombus forms and obstructs the lumen completely, or partially. This can lead to ischaemia downstream leading to an ischaemic attack in the brain, or rupture to cause a haemorrhagic stroke. Adapted from [107]
Fig. 4 Overview of the pathogenesis of atherosclerosis. Accumulation of LDLs in the blood leads to LDLs being transported into the endothelium, where they become oxidised. Infiltrating monocytes become activated and differentiate into macrophages and begin to ingest oxidised-LDLs to become foam cells. Over time, foam cells conglomerate to form fatty streaks. Simultaneously, due to inflammation and stimulant factors, VSMCs begin to proliferate and migrate into the intima and form a cap around the fatty streak. Endothelial cells overlying the growing plaque become calcified, with reduced elasticity. Over time this cap restricts blood flow due to a luminal constriction. If the plaque ruptures, a thrombus forms and obstructs the lumen completely, or partially. This can lead to ischaemia downstream leading to an ischaemic attack in the brain, or rupture to cause a haemorrhagic stroke. Adapted from [107]CC BY · PubMed Central
Fig. 5 Vascular lesions in small vessel disease. Key types of vascular lesions found in the brain as a result of small vessel disease (SVD) leading to cognitive impairment (vascular dementia) and stroke include microbleeds, microinfarcts; where fatty deposits accumulate to restrict luminal diameter, and inflammatory white matter pathology such as lipohyalinosis, where hyaline deposits within connective tissue in addition to astrocytic gliosis (scarring) and wall swelling to disrupt the uniformity of vessel walls within the brain. Adapted from [76]
Fig. 5 Vascular lesions in small vessel disease. Key types of vascular lesions found in the brain as a result of small vessel disease (SVD) leading to cognitive impairment (vascular dementia) and stroke include microbleeds, microinfarcts; where fatty deposits accumulate to restrict luminal diameter, and inflammatory white matter pathology such as lipohyalinosis, where hyaline deposits within connective tissue in addition to astrocytic gliosis (scarring) and wall swelling to disrupt the uniformity of vessel walls within the brain. Adapted from [76]CC BY · PubMed Central
Fig. 6 Summary of vascular pathologies in CVD, stroke and dementia. Vascular dysfunction pathway for stroke, vascular dementia and AD; AD-specific factors in red text (incorporating the 2-hit hypothesis for AD—hit 1 being at vessel damage and hit-2 being Aβ increase). CVD can directly cause cerebral vessel damage to cause either strokes and/or vascular dementia, in addition to initiating AD pathology if certain risk factors are present. Adapted from [21, 108]
Fig. 6 Summary of vascular pathologies in CVD, stroke and dementia. Vascular dysfunction pathway for stroke, vascular dementia and AD; AD-specific factors in red text (incorporating the 2-hit hypothesis for AD—hit 1 being at vessel damage and hit-2 being Aβ increase). CVD can directly cause cerebral vessel damage to cause either strokes and/or vascular dementia, in addition to initiating AD pathology if certain risk factors are present. Adapted from [21, 108]CC BY · PubMed Central
Fig. 7 PCSK9 mechanisms. LDL low-density lipoprotein, LDL-C cholesterol, LDLR low-density lipoprotein receptor, PCSK9 proprotein convertase subtilisin/kexin type 9, HC hypercholesterolemia, g.o.f. gain of function, FADHC familial autosomal dominant hypercholesterolemia. a (Left)—physiological homeostatic regulation of LDL-C by LDLR. a (Right)—physiological homeostatic regulation of LDLR by PCSK9 (which may lead to HC). b Genetic mutant (g.o.f.) variant of PCSK9 causing FADHC. c PCSK9 inhibitor mechanism to reduce LDL-C levels in patients with HC
Fig. 7 PCSK9 mechanisms. LDL low-density lipoprotein, LDL-C cholesterol, LDLR low-density lipoprotein receptor, PCSK9 proprotein convertase subtilisin/kexin type 9, HC hypercholesterolemia, g.o.f. gain of function, FADHC familial autosomal dominant hypercholesterolemia. a (Left)—physiological homeostatic regulation of LDL-C by LDLR. a (Right)—physiological homeostatic regulation of LDLR by PCSK9 (which may lead to HC). b Genetic mutant (g.o.f.) variant of PCSK9 causing FADHC. c PCSK9 inhibitor mechanism to reduce LDL-C levels in patients with HCCC BY · PubMed Central

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Metadata

Authors
Shabir, O., Berwick, J., & Francis, S. E.
Affiliations
University of Sheffield (GB)
Corresponding author
Shabir, Osman
ORCID
Venue
BMC Neuroscience
Publisher
Springer Science and Business Media LLC
Published
2018-10-17
Volume
19
Issue
1
Pages
62-62
ISSN
1471-2202 (ISSN-L)
DOI
10.1186/s12868-018-0465-5
PMC
PMC6192291
OpenAlex
W2896976060
Cited by
191
References
111
Citations by year
2026: 12 · 2025: 27 · 2024: 32 · 2023: 32 · 2022: 25 · 2021: 31 · 2020: 23 · 2019: 8
FWCI
1.46
Type
journal article
Language
en
Open access
Licence
Locations
  • BMC Neuroscience (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Medical Research Council (MR/M013553/1)
  • Alzheimer’s Research UK (ARUK-IRG2014)
Topics
  • Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
  • Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
  • Health Sciences › Medicine › Clinical Neurology › Traumatic Brain Injury and Neurovascular Disturbances
Keywords
neurovascular coupling, vascular dementia, Alzheimer's disease, atherosclerosis, cerebral blood flow, cerebrovascular dysfunction, stroke, cognitive decline, cerebrovascular disease
MeSH terms
Neurovascular Coupling, Alzheimer Disease, Animals, Brain, Humans, Dementia, Vascular, Atherosclerosis

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