Vascular cognitive impairment (VCI) or vascular dementia occurs as a result of brain ischemia and represents the second most common type of dementia after Alzheimer's disease. To explore the ...underlying mechanisms of VCI, several animal models of chronic cerebral hypoperfusion have been developed in rats, mice, and primates. We established a mouse model of chronic cerebral hypoperfusion by narrowing the bilateral common carotid arteries with microcoils, eventually resulting in hippocampal atrophy. In addition, a mouse model of white matter infarct-related damage with cognitive and motor dysfunction has also been established by asymmetric common carotid artery surgery. Although most experiments studying chronic cerebral hypoperfusion have been performed in rodents because of the ease of handling and greater ethical acceptability, non-human primates appear to represent the best model for the study of VCI, due to their similarities in much larger white matter volume and amyloid β depositions like humans. Therefore, we also recently developed a baboon model of VCI through three-vessel occlusion (both the internal carotid arteries and the left vertebral artery). In this review, several animal models of chronic cerebral hypoperfusion, from mouse to primate, are extensively discussed to aid in better understanding of pathophysiology of VCI.
Increasing evidence suggests that vascular risk factors contribute to neurodegeneration, cognitive impairment and dementia. While there is considerable overlap between features of vascular cognitive ...impairment and dementia (VCID) and Alzheimer's disease (AD), it appears that cerebral hypoperfusion is the common underlying pathophysiological mechanism which is a major contributor to cognitive decline and degenerative processes leading to dementia. Sustained cerebral hypoperfusion is suggested to be the cause of white matter attenuation, a key feature common to both AD and dementia associated with cerebral small vessel disease (SVD). White matter changes increase the risk for stroke, dementia and disability. A major gap has been the lack of mechanistic insights into the evolution and progress of VCID. However, this gap is closing with the recent refinement of rodent models which replicate chronic cerebral hypoperfusion. In this review, we discuss the relevance and advantages of these models in elucidating the pathogenesis of VCID and explore the interplay between hypoperfusion and the deposition of amyloid β (Aβ) protein, as it relates to AD. We use examples of our recent investigations to illustrate the utility of the model in preclinical testing of candidate drugs and lifestyle factors. We propose that the use of such models is necessary for tackling the urgently needed translational gap from preclinical models to clinical treatments.
Epidemiological investigations have proposed strict control of vascular risk factors as a strategy to overcome dementia, because of the close interaction between cerebrovascular disease (CVD) and ...Alzheimer's disease. In light of recent advances in basic, translational, and clinical research in the area, this review focuses on the significance of CVD in Alzheimer's disease pathogenesis.
Alzheimer's disease and CVD share several risk factors, and the coexistence of both pathologies is frequently noted. CVD and subsequent cerebral blood flow reduction would increase amyloid β (Aβ) production by modulating β and γ-secretase. Furthermore, CVD impairs Aβ clearance, which is mainly driven by vascular mediated systems, including active transport across the blood-brain barrier, and perivascular lymphatic/paravascular glymphatic drainage systems. Thus, CVD may disturb homeostasis between Aβ production and clearance, thereby aggravating Alzheimer's disease. Recent translational researches in this field aim to facilitate Aβ clearance. Several candidate drugs are being tested in clinical trials.
Compared with Aβ pathology, little is known about the relationship between tau pathology and CVD, although some studies have shown that CVD has an influence on tau pathology. The close interrelationship between Alzheimer's disease and CVD suggests the necessity of the maintenance of cerebrovascular integrity, which may herald a new generation of dementia treatment strategies.
Stroke is the second leading cause of death and a significant cause of disability worldwide. Recent advances in DNA sequencing, proteomics, metabolomics, and computational tools are dramatically ...increasing access to the identification of host–microbiota interactions in systemic diseases. In this review, we describe the accumulating evidence showing how human microbiota plays an essential role in cerebrovascular diseases. We introduce the symbiotic relationships between microbiota and the mucosal immune system, focusing on differences by anatomical sites. Microbiota directly or indirectly contributes to the pathogenesis of traditional vascular risk factors including age, obesity, diabetes mellitus, dyslipidemia, and hypertension. Moreover, recent studies proposed independent effects of the microbiome on the progression of various subtypes of stroke through direct microbial invasion, exotoxins, functional amyloids, inflammation, and microbe-derived metabolites. We propose the critical concept of gene-microbial interaction to elucidate the heterogeneity of stroke and provide possible therapeutic avenues. We suggest ways to resolve the vast inter-individual diversity of cerebrovascular disease and mechanisms for personalized prevention and treatment.
Cerebral amyloid angiopathy (CAA) results from amyloid-β deposition in the cerebrovasculature. It is frequently accompanied by Alzheimer’s disease and causes dementia. We recently demonstrated that ...in a mouse model of CAA, taxifolin improved cerebral blood flow, promoted amyloid-β removal from the brain, and prevented cognitive dysfunction when administered orally. Here we showed that taxifolin inhibited the intracerebral production of amyloid-β through suppressing the ApoE–ERK1/2–amyloid-β precursor protein axis, despite the low permeability of the blood–brain barrier to taxifolin. Higher expression levels of triggering receptor expressed on myeloid cell 2 (TREM2) were associated with the exacerbation of inflammation in the brain. Taxifolin suppressed inflammation, alleviating the accumulation of TREM2-expressing cells in the brain. It also mitigated glutamate levels and oxidative tissue damage and reduced brain levels of active caspases, indicative of apoptotic cell death. Thus, the oral administration of taxifolin had intracerebral pleiotropic neuroprotective effects on CAA through suppressing amyloid-β production and beneficially modulating proinflammatory microglial phenotypes.
Oligodendrocyte precursor cells (OPCs) in the adult brain contribute to white matter homeostasis. After white matter damage, OPCs compensate for oligodendrocyte loss by differentiating into mature ...oligodendrocytes. However, the underlying mechanisms remain to be fully defined. Here, we test the hypothesis that, during endogenous recovery from white matter ischemic injury, astrocytes support the maturation of OPCs by secreting brain-derived neurotrophic factor (BDNF). For in vitro experiments, cultured primary OPCs and astrocytes were prepared from postnatal day 2 rat cortex. When OPCs were subjected to chemical hypoxic stress by exposing them to sublethal CoCl2 for 7 d, in vitro OPC differentiation into oligodendrocytes was significantly suppressed. Conditioned medium from astrocytes (astro-medium) restored the process of OPC maturation even under the stressed conditions. When astro-medium was filtered with TrkB-Fc to remove BDNF, the BDNF-deficient astro-medium no longer supported OPC maturation. For in vivo experiments, we analyzed a transgenic mouse line (GFAP(cre)/BDNF(wt/fl)) in which BDNF expression is downregulated specifically in GFAP(+) astrocytes. Both wild-type (GFAP(wt)/BDNF(wt/fl) mice) and transgenic mice were subjected to prolonged cerebral hypoperfusion by bilateral common carotid artery stenosis. As expected, compared with wild-type mice, the transgenic mice exhibited a lower number of newly generated oligodendrocytes and larger white matter damage. Together, these findings demonstrate that, during endogenous recovery from white matter damage, astrocytes may promote oligodendrogenesis by secreting BDNF.
The repair of white matter after brain injury and neurodegeneration remains a tremendous hurdle for a wide spectrum of CNS disorders. One potentially important opportunity may reside in the response of residual oligodendrocyte precursor cells (OPCs). OPCs may serve as a back-up for generating mature oligodendrocytes in damaged white matter. However, the underlying mechanisms are still mostly unknown. Here, we use a combination of cell biology and an animal model to report a new pathway in which astrocyte-derived BDNF supports oligodendrogenesis and regeneration after white matter damage. These findings provide new mechanistic insight into white matter physiology and pathophysiology, which would be broadly and clinically applicable to CNS disease.
Pericytes are unique, multi-functional mural cells localized at the abluminal side of the perivascular space in microvessels. Originally discovered in 19th century, pericytes had drawn less attention ...until decades ago mainly due to lack of specific markers. Recently, however, a growing body of evidence has revealed that pericytes play various important roles: development and maintenance of blood-brain barrier (BBB), regulation of the neurovascular system (e.g., vascular stability, vessel formation, cerebral blood flow, etc.), trafficking of inflammatory cells, clearance of toxic waste products from the brain, and acquisition of stem cell-like properties. In the neurovascular unit, pericytes perform these functions through coordinated crosstalk with neighboring cells including endothelial, glial, and neuronal cells. Dysfunction of pericytes contribute to a wide variety of diseases that lead to cognitive impairments such as cerebral small vessel disease (SVD), acute stroke, Alzheimer's disease (AD), and other neurological disorders. For instance, in SVDs, pericyte degeneration leads to microvessel instability and demyelination while in stroke, pericyte constriction after ischemia causes a no-reflow phenomenon in brain capillaries. In AD, which shares some common risk factors with vascular dementia, reduction in pericyte coverage and subsequent microvascular impairments are observed in association with white matter attenuation and contribute to impaired cognition. Pericyte loss causes BBB-breakdown, which stagnates amyloid β clearance and the leakage of neurotoxic molecules into the brain parenchyma. In this review, we first summarize the characteristics of brain microvessel pericytes, and their roles in the central nervous system. Then, we focus on how dysfunctional pericytes contribute to the pathogenesis of vascular cognitive impairment including cerebral 'small vessel' and 'large vessel' diseases, as well as AD. Finally, we discuss therapeutic implications for these disorders by targeting pericytes.
Early detection of hemorrhagic transformation after reperfusion therapy is crucial in acute stroke treatment. Here, we evaluated the relationship between hemorrhagic transformation and ...post-reperfusion hyperperfusion using pulsed arterial spin labeling (ASL) perfusion MRI and 123I-iodoamphetamine single-photon emission-computed tomography. Patients who developed hemorrhagic transformation showed significantly higher cerebral blood flow in the affected lesion after thrombolysis and/or endovascular intervention. Focal hyperperfusion (ipsilateral to contralateral ratio >1.5) was associated with hemorrhagic transformation after reperfusion (odds ratio, 9.3; 95% confidence interval, 1.4–64.0). Our findings suggest that post-reperfusion hyperperfusion on ASL could represent a reliable marker of hemorrhagic transformation.
We investigated the potential of mid-regional pro-adrenomedullin (MR-proADM) for use as a novel biomarker for arterial stiffness as the criterion for vascular failure and cardiometabolic disease ...(obesity, hypertension, dyslipidemia, diabetes, and metabolic syndrome) compared with high-sensitivity C-reactive protein (hsCRP). Overall, 2169 individuals (702 men and 1467 women) were enrolled. Multiple regression analysis was performed to assess the association of MR-proADM and hsCRP with brachial-ankle pulse wave velocity (baPWV), adjusting for other variables. The diagnostic performance (accuracy) of MR-proADM with regard to the index of vascular failure was tested with the help of receiver operating characteristic curve analysis in the models. MR-proADM was significantly higher in participants with vascular failure, as defined by baPWV and/or its risk factors (obesity, hypertension, dyslipidemia, diabetes, and metabolic syndrome), than in control groups. Independent of cardiovascular risk factors (age, drinking, smoking, body mass index, systolic blood pressure, lipid and glycol metabolism), MR-proADM was significantly associated with baPWV, and MR-proADM showed higher areas under the curve of baPWV than hsCRP showed. MR-proADM is more suitable for the diagnosis of higher arterial stiffness as the criterion for vascular failure than hsCRP. Because vascular assessment is important to mitigate the most significant modifiable cardiovascular risk factors, MR-proADM may be useful as a novel biomarker on routine blood examination.
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