Advances in the Pathogenesis of Vascular Cognitive Impairment

Meng Geng,Yao-Ming Xu＊

1Department of Neurology,Tongliao Sity Hospital of Inner Mongolia,TongLiao,China.

2Tongliao Clinical Medical College,Inner Mongolia Medical University,TongLiao,China.

Abstract

As the population ages,the number of patients with vascular cognitive impairment(VCI)increases,which increases the burden on patient's family and social.At present,the treatment and pathogenesis of VCI is still unclear.This paper reviews the literature on VCI pathogenesis,especially the molecular mechanism(oxidative stress,endoplasmic reticulum stress,inflammation,autophagy.),aiming to provide direction and reference for VCI pathogenesis research and target therapy.

Keywords:Vascular cognitive impairment,Oxidative stress,Endoplasmic reticulum stress,Inflammation,Autophagy

Introduction

The concept of vascular cognitive impairment(VCI)was first proposed by Professors Hachinski and Bowler in 1993.After continuous evolution and update,Luo BY[1]et al.pointed to the latest definition.That is VCI is characterized by cognitive impairment caused by cerebrovascular lesions and their risk factors,involving at least one clinical syndrome with impaired cognitive domain,from mild cognitive impairment to vascular dementia(VD),as well as cognitive impairment of varying degrees caused by mixed pathologies.Among them,VD is generally considered to be the second most common type of dementia subtype after Alzheimer's disease,accounting for about 15 to 20 per cent of dementia cases in North America and Europe,and is estimated to be about 30 per cent in Asia[2].Domestic epidemiology shows that the overall prevalence of mild cognitive impairment was 20.8% in the elderly population over 65 years of age in China,and the prevalence of VD was 1.5%[1].China's population base is large,with the aging of the population,the number of patients with VCI increases year by year,which brings a heavy burden to the families and society of patients.Therefore,it is of great value and significance to study the pathogenesis of VCI in the search for effective prevention and treatment methods.In the past few years,the study of the pathogenesis of VCI has become a hot topic.This paper,by combing through the literature in recent years,expounds the pathogenesis of VCI in a relatively systematic way from the perspective of molecular biology mechanism,which provides reference for VCI research and prevention.

Molecular mechanism of vascular cognitive impairment

The study shows[3-7]that the factors that can cause cerebrovascular damage include age, smoking,hyperlipidemia, hypertension, atrial fibrillation,coronary heart disease,diabetes and hyperthyroidism.The mechanism of cognitive impairment may be related to oxidative stress,inflammation,apoptosis,etc.VCI's pathogenesis is complex,which involves neurocytoplasmosis,mitochondrial oxidative stress,endoplasmic mesh stress,autophagy,inflammation and other ways.In addition,recent studies have shown[8-15]that chronic hypoencephaloination,ischemic re-perfusion damage can cause neuronal damage and lesions through neurotransmitter disorders,oxidative stress,neuritis reactions and other mechanisms,leading to neurodegenerative changes and cognitive dysfunction.

VCI and mitochondrial oxidative stress

In the study of vascular dementia,neurocellular apoptosis has been paid more and more attention.The cerebral hippocoma CA1 region is sensitive to ischemic and hypoxia,is the most closely related functional area with learning memory in hippocular tissue,the survival of hippocular neurons directly affects the storage and processing of information by hippocular neurons[9].A large number of neurons in the hippocular region of vascular dementia are lost,and the loss of apoptosis of hippocular neurons is one of the pathological bases of the onset of vascular dementia[10].There is ample evidence that oxidative stress and its induced apoptosis play a key role in the process of brain ischemic neuronal injury.Oxidative stress is when oxides exceed the original antioxidant capacity of the body,causing the molecular oxidation of tissues,resulting in apoptosis and death.The study found elevated levels of hyperoxygenic anions,hydroxy free radicals,H2O2,nitric oxide(NO)and other free radicals during stroke,antioxidant enzymes,superoxide dismutase(SOD),glutathione peroxidase,and hypergenic antioxidant systems were found to be high Hydrogen oxide enzyme,while glutathione,vitamin C,vitamin E(α-tocopherol)content decreased[11],which makes the body's oxidation system and antioxidant system imbalance,induced oxidative stress caused neuronal damage.Among them,ischemic,hypoxic mitochondria release more causes reactive oxygen species(ROS).ROS damages cells in a variety of ways:(1)ROS can cause membrane lipid peroxidation,damage membrane integrity,thereby directly damaging cells;(2)ROS causes dysfunction of peroxidase,which reduces ROS removal and increases damage to cells.(3)ROS reacts with NO to produce peroxygen nitrites,weakening the role of NO,but also nitroproteins and other biomolecules,causing cell dysfunction.(4) ROS activates the apoptosis mechanism of the cells and indirectly damages the cells[12].In addition,the reduction of ATP in ischemia and hypoxia can reduce the activity of Mn-SOD,resulting in a decrease in free radical removal capacity,thereby aggravating oxidative stress.Oxygen free radicals act on the lipids,proteins and DNA of mitochondria,causing oxidative damage that affects the function of electron delivery and impairs the structure and function of mitochondria.Mitochondrial damage leads to a vicious cycle and release more ROS,which in turn induces apoptosis and necrosis of nerve cells,causing cognitive damage.

VCI and endoplasmic network stress

Regarding the pathogenesis of VCI,vascular factors are the initiation factors,and in the process of VCI-VD progression,many mechanisms are considered to be involved, such as chronic hypoentic perfusion,ischemic re-perfusion injury, oxidative stress,inflammatory response.Studies have shown that endoplasmic reticulum stress(ERS)plays an important role in the development of VD[13].The endoplasmic mesh is an important organelle in cells that is involved in the correct folding and secretion of proteins.ERS occurs when abnormal proteins accumulate in the body beyond the transcription function of the endoplasm reticulum.ERS can be induced under the influence of factors such as lack of sugar and oxygen,calcium imbalance, oxidative stress and toxins.The endoplasmic mesh stress in the early acute stage is an adaptive reaction of the body in the state of stress,which plays a beneficial role in the pathological process of the disease.However, persistent endoplasmic network stress exceeds the body's ability to recognize,triggering apoptosis,which leads to the development of disease.ERS-mediated apoptosis has its own signaling pathways,namely CHOP pathways,Caspase pathways,and JNK pathways.These three pathways can independently induce apoptosis and also work together.CHOP is a specific pathway for ERS to induce apoptosis.CHOP overexpression promotes apoptosis through mitochondrial pathways,on the one hand,increases the expression of the apoptosis protein Bax,on the other hand inhibits the expression of the anti-apoptosis protein Bcl-2[14].Caspase-3 is the downstream executive factor of Caspase's apoptosis cascade reaction,which is activated to promote apoptosis.Cerebral ischemia is an important factor in the damage to the endoplasmic network of nerve cells,especially when re-injected[15].In recent years,many studies have shown that ERS plays an important role in neuronal damage during ischemic re-perfusion, and inhibiting ERS-induced neuronal apoptosis protects brain tissue from ischemic re-perfusion damage[16].Wu et al[15].established a brain ischemia re-perfusion model in rats and found that ERS markers such as GRP78,CHOP/GADD153 and cysteine protease-12 expressed higher level significance;After the intervention of pinein,CHOP/GADD153 and caspase-12 expression decreased;GRP78 expression continued to increase.GRP78 is an important molecular companion of the endoplasmic network,and its addition is conducive to the correct folding of proteins.Several studies in recent years have shown that ERS is related to brain injury;but there is little evidence of direct link between endoplasmic network stress and VCI,which provides a new direction for the study of VCI pathogenesis.

VCI and inflammation

Vascular damage causes an immune inflammatory response that restores tissue to normal after repair;but a sustained immune response can exacerbate vascular damage and alter the inflammatory response process throughout the body.Vascular changes affect innate immunity,which then activates white blood cells and antigen presentation cells.Inflammatory responses promote post-stroke neuronal degeneration and death by activating immune cells(small glial cells,mononuclear macrophages,etc.)to inundate and secrete inflammatory factors and neurotoxic products such as IL-6, IL-1β, TNF-α.Under normal physiological condition,the phenoplasty of small glial cells is regulated by neurons and astrocytes,so that their phagocytosis activity is in a regulatable state.After the central nervous system is stimulated by ischemia of the brain,small glial cells rapidly activate and proliferate,responding to this stimulation through an inflammatory response[17].IL-1β,TNF-α play an important role in the body's immune regulation and inflammatory response[18].TNF-α is a neurotoxin produced by stimulation of small glial cells,which has an excitatory toxic effect on neurons by increasing glutamate levels.TNF-α also promotes the production of IL-6 and IL-1β in small glial cells.IL-1β promotes an increase in the number and activity of small glial cells through self-secretion,which in turn leads to an increase in chemokines,inflammatory media and cytokines.These increased pro-inflammatory factors can further activate small glial cells,increasing their inflammatory response,forming a vicious circle leading to pathological damage to nerve cells,and ultimately leading to varying degrees of cognitive impairment.The results of animal experiments showed that the TNF-α and IL-1β levels in the VCI model hippocoma were significantly higher than in normal rats,and abnormal changes in neuronal morphology and cognitive function were reduced[19,20].Clinical studies have shown that the levels of TNF-α and IL-1β in the brain of VCI patients were significantly higher than in non-VCI patients[21,22].In recent years,there have also been clinical studies[23,24]to prove that the degree of VCI in patients with hypertension cerebrovascular disease is related to the level of sero inflammatory factors,and the higher the level of sero inflammatory factors,the heavier the degree of VCI.These results show that the occurrence of VCI may be related to inflammatory factors.Changes in blood vessels also promote the production of reactive oxygen and the release of undesirable proteins such as matrix metalloproteinase(MMP),MMP-2,MMP-3 and MMP-9.These released ingredients destroy the extracellular matrix,induce vascular wall remodeling,disrupt tightly connected protein function, and ultimately lead to the destruction of the blood-brain barrier and white matter.Hypoxia was observed in the case of double-sided cervical aorta occlusion and spontaneous hypertension stroke,which was also another key factor in promoting inflammatory MMPs release[25-27].

In addition, studies have shown that ischemic-induced inflammatory reactions may be an important pathological mechanism for chronic low perfusion brain injury[28].Inflammatory reaction process can remove dead cells and initiate related repair process,to protect the body;but inflammatory reaction can also have many adverse effects on the body.Related studies have found that chronic low-perfusion status can lead to activation and proliferation of small glial cells and astrocytes in rat brain tissue[29].Overactive small glial cells can aggravate brain damage and lead to cognitive impairments such as learning and memory in the brain.Similarly,long-term low-perfusion of the brain can activate star-shaped glial cells to release nitric oxide and inflammatory cytokines such as TNF-a,IL-6 and IL-1β,and participate in the pathophysiological process of the immune response in the brain.Astrocytes also activate NLRP1,NLRP2,NLRP3,and AIM2 inflammatory small bodies in the amygdala and stimulate the production of pro-inflammatory cytokines[30].Among them,IL-1β is a typical multi-effect inflammatory cytokine,which has a wide range of effects on immune signals,central nervous system function and cognitive function.Chronic hypothalimation can induce an increase in the expression of IL-1β,which causes a vicious cycle of inflammatory reactions that act on special neurons such as the hippocum,leading to cognitive impairment.Other studies have shown that the number of star-shaped glial cells and small glial cells activated in the cerebral cortex and hippocoma regions in rats is significantly associated with protein niobium-based content,suggesting that activated glial cells may help increase oxidative stress damage.Therefore,glial cell activation and inflammatory reactions caused by chronic low perfusion may be associated with cognitive dysfunction[31].

Receptor for glycation end products(RAGE)is activated in chronic hypothalamus and vascular damage and is present in large numbers in the hippocca,the inner temporal lobe,and small glial cells and neurons back to the frontal lobe and edges of the brain.RAGE is a multi-ligand receptor that activates several signaling pathways by binding to the corresponding ligand,affecting the body's immune defenses and wound healing,and participating in a vicious cycle of inflammation.RAGE induces transcription activation of the signaling pathway of the nuclear factor kappa-light-chainenancer of activated B cells(NF-κB)to increase the levels of pro-inflammatory cytokines and inflammatory small bodies,and stimulates inflammatory signals [32].The RAGE NF-κB cross-act eventually leads to the activation of the IκB kinase,which phosphorylates the IκB and inhibits the progression of the NF-κB pathway.RAGE also activates Toll-like receptors, which are usually abundant in macrophages and dendritic cells and are connected to innate and adaptive immunity[33].In addition,RAGE stimulates phosphorylation of the inositol 3 kinase(PI3K)/Akt,Jun-N-end kinase(JNK),p38,and extracellular signaling-regulating kinase(ERK) pathways,ultimately promoting vascular stress-induced inflammation and dementia.The intersection of these signaling pathways stimulates the overactivation of small glial cells,astrocytes and macrophages in the brain,leading to degeneration of endothopheric cells and neurons and damage to the blood-brain barrier.

VCI and autophagy

Autophagy is a cell in the memory of a large number of longevity proteins and functional damage of the organelle,by the lysosome mediated activation and degradation of such longevity proteins and damaged organelles,and recycling,is the process of cell self-cleaning adjustment,maintenance of steady state.Autophagy has long been regarded as an adaptive protective mechanism of cells,in the case of hypoxic ischemia,oxidative stress and other pathological conditions,recycling waste to produce energy and metabolic basic substances.Su et al.[34]applied autophagy inhibitors to the hypoxic ischemia model of newborn mice for the first time,and observed rapid necrosis of cells after inhibiting ischemic isaxia after autophagy,suggesting that autophagy is a potential and universal protective mechanism.Autophagy activity is important for cell survival in the process of ischemic hypoxic brain damage.Autophagy uses antioxidants,resveratrol,inactivated AKT and mTOR,as well as its downstream ribosome protein S6 kinase β-1(S6K1)and eukaryotic translation starting factor 4e binding protein 1(4E-BP1)expression and phosphorylation to play neuroprotective role[35].In the animal model of bi-lateral aortic stenosis(BCAS),vascular dementia raised the levels of AKT and mTOR phosphorylation induced by oxidative stress.In fact,dephosphate of phosphorylation phosphatase and tension isogenes(PTEN)is the cause of AKT(thr308)and mTOR activation.In addition, in the BCAS model,antioxidants promote autophagy and regulate the mTOR pathway by lowering PTEN and Raptor levels,leading to hippocult recovery.Zocanitin-induced axon plasticity and reduced cognitive dysfunction are involved in the control of the Pten/Akt/mTOR pathway after chronic cerebral perfusion deficiency.It is speculated that the reduction in mTOR actually inhibits the autophagy process of neurons in rats,eventually leading to vascular dementia.Both LC3 and P62 were increased in both BCAS and Antioxidant plus BCAS model groups.However,p62-depeandent creatine phosphate-dependent protein kinase1(PDK1)is expressed in the BCAS-antioxidant model,thereby reducing neuronal apoptosis by[36].The protective effect of PI3/AKT pathway on mir-21-mediated low oxygen/regenerative damage has even been reported.MiR-23b targets the autophagy marker ATG12 3'-a potential sequence in a non-translated region that binds to the anti-apoptosis protein Bcl2 and promotes neuronal cell death.During chronic hypothalamus,miR-96 increases in the brain,while inhibition of miR-96 through normal expression of mTOR prevents nerve behavioral damage[37].Sheng et al.[38]found that before artery ligation in the brain,the brain pre-injected rapamycin or 3-MA,the former activates autophagy,cerebral infarction volume,cerebral edema,reduced movement disorders,3-MA group LC3,Beclin-1 expression decreased;inhibited autophagy,brain damage increased.Studies have shown[39]that in mouse stroke models,ischemic pretreatment activates neuronal autophagy in advance,significantly reducing apoptosis.All the above studies have shown that activating autophagy early can play a protective role after hypoxic ischemia in the brain.

Moderate autophagy in the early stages of ischemic hypoxia can play a neuroprotective role;but late autophagy overactivation can damage neurons.For example,long-term hypothalapal injection induced vascular dementia and is under-activated autophagy triggered in the brain pathogenic process and synaptic activity loss [40].Long-term cerebral perfusion deficiency and subsequent vascular pathological manifestations were also associated with elevated levels of hippochorma LC3-II/LC3-I.3-MDMA-mediated autophagy inhibition restores normal synaptic reconstruction and growth,especially in the hippocoma,which controls synaptic size distribution and memory[40,41].Descloux et al.[42]established a model of brain damage in newborn mice and neuroexcited toxin goosepasine culture progenitic cortical neurons;24 h after detecting neuronal autophagy enhancement,pre-injection 3-MA not only inhibited autophagy,but also inhibited the activity of Caspase-3 and brain damage significantly reduced.The same results were obtained in in vitro experiments.Similarly,heptafluoroethyl treated HIE rats and found that the brain was inhibited by ERK cascade over-autophagy,reducing brain damage[43].All of the above have been shown to cause brain damage from overactive autophagy.In addition,the expression of calcium binocin synapses(Syn)and post-synaptic density protein-95(PSD95)in the hippoculous tissue of angiovascular dementia decreased,while calcium binocyte synapses and post-synaptic density protein-95 regulate synaptic function and synaptic transmission and growth.Autophagytic inducor Rapamycin increases the absence of Syn and PSD-95,aggravating vascular dementia-induced synapses and changes in hippocampus plasticity.Thus,blocking autophagy not only reduces autophagy levels and neuronal damage,but also reduces cognitive dysfunction in vascular diseases.Similar studies have shown that increased expression of the hippocellobacteriophage markers Beclin-1 and lysosome enzyme cathepsin-B strongly stimulates the development and progression of vascular dementia[41].Therefore,autophagy may be a potential therapeutic target after ischemic hypoxia.The study found[44]that heptafluoroe ether anaesthetic can significantly impair the memory ability of elderly rats,induce hippocampus neurons to apoptosis,and combined rapamycin therapy can improve heptafluoroe ether induced autophagy channel damage.It has been shown that heptafluoroe ether anesthesia causes cognitive dysfunction in older rats to be associated with impaired autophagy in hippocampus neurons.Many studies in recent years have shown that brain damage and cognitive impairment are related to autophagy;but there are few studies on the link between VCI and autophagy,so the association between autophagy and VCI has become a hot topic.Recent studies have studied the neuroprotective effect of ischemic processing activation autophagy on ischemic re-perfusion caused by VCI,and have also provided a new direction for the study of VCI mechanisms and treatments.

Recent studies have been conducted involving the synchronous activation of autophagy,inflammation,and apoptosis in the development and pathogenesis of vascular dementia,characterized by the simultaneous stimulation of LC3-II and beclin-I proteins,NLRP3,IL-1,and caspase.These three processes are also activated in a sequential and interdependent manner.Iron dysregulation also plays a key role in vascular dementia,with both autophagy and apoptosis involved in hippocampal neurons[45].The permanent BCAO model showed iron content increased and dysregulation of iron homeostasis, along with expression of iron transport-related molecules in the hippocampus(transferrin receptor-3 and divalent metal transporter-1) enhanced.Increased iron content appears to be a key reason for the increased expression of autophagy regulators and markers AMPK,Beclin1,LC3,and the autophagosome.Increased hippocampal iron content detected in the Morris water maze test led to upregulated Bax and reduced Bcl2 levels[45].In vascular dementia,there is also a direct link between inflammation and apoptosis, which eliminates apoptosis and downregulates oxidative stress by knocking down TLR4 and inhibiting NF-B signaling.In neurobehavioral trials of mouse carotid occlusion models of cerebellar vascular disease,reductions in inflammatory events reduced the number of errors and modulated latency[46].

Conclusion

In conclusion,the pathogenesis of VCI remains unclear,and mechanistic studies need to continue in the future.The current studies of key molecules in the autophagy pathway, inflammatory pathway, mitochondrial oxidative stress,such as autophagy breakdown products, intracellular pathogens, damaged mitochondria,and NLRP3 inflammasomes,which are capable of causing neuronal damage.Therefore,these key molecules serve as targets providing new ways for the treatment of VCI.To prevent VCI,it is important to study the mechanism underlying the causes of VCI;but the determination of therapeutic targets according to the molecular mechanism of VCI has been a future research direction.Therefore,these previous studies provide important reference for the future mechanistic research and treatment of VCI.