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Molecular Mechanisms of Vascular Dementia: What Can Be Learned from Animal Models of Chronic Cerebral Hypoperfusion?

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Abstract

Vascular dementia (VD) is defined as a progressive neurodegenerative disease of cognitive decline, attributable to cerebrovascular factors. Numerous studies have demonstrated that chronic cerebral hypoperfusion (CCH) is associated with the initiation and progression of VD and Alzheimer’s disease (AD). Suitable animal models were established to replicate such pathological condition in experimental research, which contributes largely to comprehending causal relationships between CCH and cognitive impairment. The most widely used experimental model of VD and CCH is permanent bilateral common carotid artery occlusion in rats. In CCH models, changes of learning and memory, cerebral blood flow (CBF), energy metabolism, and neuropathology initiated by ischemia were revealed. However, in order to achieve potential therapeutic targets, particular mechanisms in cognitive and neuropathological changes from CCH to dementia should be investigated. Recent studies have shown that hypoperfusion resulted in a chain of disruption of homeostatic interactions, including oxidative stress, neuroinflammation, neurotransmitter system dysfunction, mitochondrial dysfunction, disturbance of lipid metabolism, and alterations of growth factors. Evidence from experimental studies that elucidate the damaging effects of such imbalances suggests their critical roles in the pathogenesis of VD. The present review provides a summary of the achievements in mechanisms made with the CCH models, permits an understanding of the causative role played by CCH in VD, and highlights preventative and therapeutic prospects.

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Abbreviations

VD:

Vascular dementia

CBF:

Cerebral blood flow

AD:

Alzheimer’s disease

2VO:

Two-vessel occlusion

CCH:

Chronic cerebral hypoperfusion

WM:

White matter

1VO:

One-vessel occlusion

2VO:

Two-vessel occlusion

3VO:

Three-vessel occlusion

4VO:

Four-vessel occlusion

BCAS:

Bilateral common carotid artery stenosis

ROS:

Reactive oxygen species

O2−:

Superoxide anions

−OH:

Hydroxyl radical

H2O2 :

Hydrogen peroxide

MDA:

Malondialdehyde

4-HNE:

4-hydroxy-2-nonenal

8-OHdG:

8-hydroxy-deoxyguanosine

SOD:

superoxide dismutase

GPx:

Glutathione peroxidase

GST:

Glutahione-S-transferase

GR:

Glutathione reductase

NQO1:

NAD(P)H: Quinone Oxidoreductase1

GSH:

Glutathione

CNS:

Central nervous system

AA:

Ascorbic acid

Nox:

Nicotinamide adenine dinucleotide phosphate oxidase

Nrf2:

Nuclear factor-erythroid 2-related factor-2

HO-1:

Heme oxygenase-1

ARE:

Antioxidant response element

ERK:

Extracellular signal regulated kinase

RAS:

Rrenin-angiotensin system

AT1:

Angiotensin II type 1

CNS:

Central nervous system

CSF:

Cerebrospinal fluid

Jak:

Janus kinases

STAT:

Signal transducers and activators of transcription

IL-1β:

Interleukin-1β

TNF-α:

Tumor necrosis factor-α

MCP-1:

Monocyte chemoattractant protein-1

NF-κB:

Nuclear factor-kappaB

TLR4:

Toll-like receptor 4

MyD88:

Myeloid differentiation factor 88

MAPK:

Mitogen-activated protein kinase

A1ARs:

A1 adenosine receptors

A2ARs:

A2 adenosine receptors

VCAM-1:

Vascular cell adhesion molecule 1

ICAM-1:

Intercellular adhesion molecule 1

MMP:

Matrix metalloproteinase

BBB:

Blood brain barrier

OPCs:

Oligodendrocyte precursor cells

Ach:

Acetylcholine

DA:

Dopamine

GABA:

Gamma-aminobutyric acid

ChAT:

Choline acetyltransferase

AChE:

Acetylcholinesterase

mACh-R:

Muscarinic acetylcholine receptor

GAD67:

Glutamic acid decarboxylase 67

EAAT2:

Excitatory amino acid transporters 2

TH:

Tyrosine hydroxylase

GABAR:

GABA receptor

NMDA:

N-methyl-D-aspartic acid

ATP:

Adenosine 5’-triphosphate

ADP:

Adenosine 5’-diphosphate

AMP:

Adenosine 5’-monophosphate

PDH:

Pyruvate dehydrogenase

ETC:

Electron transfer chain

RCI:

Respiratory control index

uFA:

Unesterified fatty acids

cPLA2:

Cytosolic phospholipase A2

sPLA2:

Secretory phospholipase A2

LXR-α:

Liver X receptor-α

RXR-α:

Retinoic X receptor-α

ABCA1:

ATP-binding cassette transporter

apo A1:

apolipoprotein A1

BDNF:

Brain derived neurotrophic factor

NGF:

Nerve growth factor

VEGF:

Vascular endothelial growth factor

IGF-1:

Insulin-like growth factor-1

PDGFα:

Platelet-derived growth factor-α

bFGF:

Basic fibroblast growth factor

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Acknowledgments

This work was supported by the National Natural Science Foundation of China (no. 81303122 and no. 81473501).

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Authors and Affiliations

  1. Acupuncture and Moxibustion Department, Beijing Hospital of Traditional Chinese Medicine affiliated to Capital Medical University, 23 Meishuguanhou Street, Dongcheng District, Beijing, 100010, China

    Si-Qi Du, Xue-Rui Wang, Wen Zhu, Tian He & Cun-Zhi Liu

  2. Beijing University of Chinese Medicine, 11 Beisanhuan East Road, Chaoyang District, Beijing, 100029, China

    Ling-Yong Xiao & Jian-Feng Tu

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  1. Si-Qi Du
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Du, SQ., Wang, XR., Xiao, LY. et al. Molecular Mechanisms of Vascular Dementia: What Can Be Learned from Animal Models of Chronic Cerebral Hypoperfusion?. Mol Neurobiol 54, 3670–3682 (2017). https://doi.org/10.1007/s12035-016-9915-1

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