White matter damage as a consequence of vascular dysfunction in a spontaneous mouse model of chronic mild chronic hypoperfusion with eNOS deficiency (original) (raw)
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Research Square (Research Square), 2021
Background: Vascular cognitive impairment and dementia (VCID) is the second most common form of dementia after Alzheimer's disease (AD). Currently, the mechanistic insights into the evolution and progression of VCID are not fully understood. White matter change represents an invariant feature of both VCID and AD. Compelling clinical neuroimaging and pathological evidence suggest a link between white matter changes and neurodegeneration. Our prior study detected non-perfusion lesions in mice with partial de ciency of endothelial nitric oxide (eNOS) expression at a very young age. These lesions developed in multiple brain regions in an age-dependent manner, precisely matching to those hypoperfused areas identi ed in preclinical AD patients (i.e., temporoparietal and retrosplenial granular cortexes, and hippocampus). We therefore reasoned that eNOS-de cient mice could serve as a spontaneous model of chronic hypoperfusion. Methods/Results: White matter tracts are particularly susceptible to the vascular damage induced by chronic hypoperfusion. Using immunohistochemistry, we detected massive demyelination in the middle aged eNOS-de cient mice. The demyelinated areas were con ned to cortical and subcortical areas including the corpus callosum and hippocampus, but did not involve the striatum. The intensity of demyelination correlated with behavioral gait de cits. By Evans blue angiography, we detected bloodbrain barrier (BBB) leakage as another early pathological change affecting frontal and parietal cortex in eNOS-de cient mice, which occurs in as early as 3-4 months of age. Sodium nitrate forti ed drinking water provided to young and middle aged eNOS-de cient mice completely prevented non-perfusion, BBB leakage, and white matter pathology, indicating that impaired endothelium-derived NO signaling may have caused these pathological events. Conclusions: Using eNOS-de cient mice, we identi ed BBB breakdown and non-perfusion as the two earliest pathological events, resulting from insu cient vascular NO signaling. We speculate that the compromised BBB and chronic hypoperfusion trigger vascular damage, along with oxidative stress and astrogliosis, accounting for the white matter pathological changes in the eNOS-de cient mouse model.
Annals of the New York Academy of Sciences, 2000
Nitric oxide (NO) is an important signaling molecule that is generated through the catalytic activity of nitric oxide synthase (NOS). In the brain, NO mediates neuronal survival, synaptic plasticity, vascular smooth muscle relaxation, and endothelial cell permeability. Previous studies demonstrated aberrant expression of the NOS-III gene in neurons and glial cells in brains with Alzheimer's disease (AD). Since NOS-III is also expressed in vascular cells, and cerebrovascular disease (CVD) frequently complicates the pathology of AD, we investigated the role of NOS-III in relation to CVD in AD. Vasculopathy in AD + CVD was characterized by thickening and hyalinization of the media of small and medium-size vessels, variable degrees of beta-amyloid (A beta) deposition, and increased apoptosis of vascular smooth muscle and endothelial cells, particularly involving white matter vessels. These abnormalities were correlated with reduced levels of NOS-III expression in cerebral vessels. Double-labeling studies demonstrated that the low levels of cerebrovascular NOS-III were associated with increased levels of the pro-apoptosis gene product, p53 in smooth muscle and endothelial cells, suggesting a role for altered NOS-III expression in AD-associated vascular degeneration. Constitutively reduced cerebrovascular NOS-III expression and NO production could also lead to cerebral hypoperfusion due to impaired vasodilation responses, and diminished capacity to remove respiratory waste products and toxins from the extracellular space due to reduced capillary permeability. The role for phosphodiesterases as modulators of NOS activity is discussed, as these molecules represent potential therapeutic targets given their cell type and cyclic nucleotide specificities of action.
Brain and Behavior
IntroductionEndothelial nitric oxide synthase (eNOS) produces nitric oxide, which is essential for a variety of physiological functions in the brain. Previous work has demonstrated the detrimental effects of eNOS deficiency on brain function in male eNOS knockout (eNOS KO) mice. However, the effect of eNOS deficiency on brain structure and any association between these effects and sex is unknown.MethodsThis study used three‐dimensional high‐resolution ex vivo magnetic resonance imaging and behavioral tests of anxiety and cognitive performance to investigate structure–function relationships in the brain of female and male eNOS KO mice in young adulthood.ResultsWhile there were no differences in anxiety‐like behavior or locomotion, there was a sex‐specific deficit in contextual fear memory retention in male, but not in female, eNOS mice compared to wild‐type controls. Moreover, we found that eNOS deficiency induced changes in multiple brain regions that are involved in learning and fe...
Evidence that Alzheimer's disease is a microvascular disorder: the role of constitutive nitric oxide
Brain Research Reviews, 2000
Evidence is fast accumulating which indicates that Alzheimer's disease is a vascular disorder with neurodegenerative consequences rather than a neurodegenerative disorder with vascular consequences. It is proposed that two factors need to be present for AD to develop: (1) advanced ageing, (2) presence of a condition that lowers cerebral perfusion, such as a vascular-risk factor. The first factor introduces a normal but potentially insidious process that lowers cerebral blood flow in inverse relation to increased ageing; the second factor adds a crucial burden which further lowers brain perfusion and places vulnerable neurons in a state of high energy compromise leading to a cascade of neuronal metabolic turmoil. Convergence of the two factors above will culminate in a critically attained threshold of cerebral hypoperfusion (CATCH). CATCH is a hemodynamic microcirculatory insufficiency that will destabilize neurons, synapses, neurotransmission and cognitive function, creating in its wake a neurodegenerative state characterized by the formation of senile plaques, neurofibrillary tangles, amyloid angiopathy and in some cases, Lewy bodies. Since any of a considerable number of vascular-related conditions must be present in the ageing individual for cognition to be disturbed, CATCH identifies an important aspect of the heterogeneic disease profile assumed to be present in the AD syndrome. It is proposed that CATCH initiates AD by distorting regional brain capillary structure involving endothelial cell shape changes and impairment of nitric oxide (NO) release which affect signaling between the immune, cardiovascular and nervous systems. Evidence is presented that in many tissues there is a basal level of NO being produced and that the actions of several signaling molecules may initiate increases in basal NO levels. Moreover, these temporary increases in basal NO levels exert inhibitory cellular actions, via cellular conformational changes. Findings indicate that (a) constitutive NO is responsible for a basal or 'tonal' level of NO; (b) this NO keeps particular types of cells in a state of inhibition and (c) activation of these cells occurs through disinhibition. Consequently, tissues not maintaining a basal NO level are more prone to excitatory, immune, vascular and neural influences. Under such circumstances, these tissues cannot be down-regulated to normal basal levels, thus prolonging their excitatory state. Thus, the clinical convergence of advanced ageing in the presence of a chronic, pre-morbid vascular risk factor, can, in time, contribute to an endotheliopathy involving basal NO deficit, to the degree where regional metabolic dysfunction leads to cognitive meltdown and to progressive neurodegeneration characteristic of Alzheimer's disease.
In vivo (Athens, Greece)
Nitric oxide (NO) is a key bioregulatory active molecule in the cardiovascular, immune and nervous systems, synthesized through converting L-arginine to L-citrulline by NO synthase (NOS). Research exploration supports the theory that this molecule appears to be one of the key factors for the disruption of normal brain homeostasis, which causes the development of brain lesions and pathology such as in Alzheimer's disease (AD). Especially the vascular content of NO activity appears to be a major contributor to this pathology before the overexpression of NOS activity in other brain cellullar compartments develop. We theorize that pharmacological intervention using NO donors and/or NO suppressors should delay or minimize brain lesion development and further progression of brain pathology and dementia.
International Journal of Neurology Research, 2015
In recent years significant overlap between cardio-metabolic risk factors and cognitive decline has been reported. Cardio-metabolic and vascular factors shown to be associated with Alzheimer's disease (AD) and other forms of dementia include midlife diabetes and hypertension, cerebrovascular lesions, diminished vascular function, dyslipidemia, obesity, and cigarette smoking. Accordingly, it has been recently proposed that amyloid is not the cause of AD but merely a marker and a later consequence of upstream changes that lead to neuronal and synaptic losses. However, although the idea that features of vascular dysfunction and injury are present in cognitive decline and AD patients was suggested over 25 years ago, the role of cardio-metabolic and cerebrovascular mechanisms in the pathogenesis of AD is far from being fully elucidated. Based on newly proposed vascular hypothesis, there is an impaired structure and function of cerebral blood vessels and cells in patients with cognitive decline and AD which is mediated by vascular oxidative stress. Consistent with these observations, the importance of endothelial dysfunction in the development of AD has been highlighted. One of the most prominent features of endothelial dysfunction is decreased production and bioavailability of Nitric
Nitric Oxide: Exploring the Contextual Link with Alzheimer’s Disease
Oxidative Medicine and Cellular Longevity, 2016
Neuronal inflammation is a systematically organized physiological step often triggered to counteract an invading pathogen or to rid the body of damaged and/or dead cellular debris. At the crux of this inflammatory response is the deployment of nonneuronal cells: microglia, astrocytes, and blood-derived macrophages. Glial cells secrete a host of bioactive molecules, which include proinflammatory factors and nitric oxide (NO). From immunomodulation to neuromodulation, NO is a renowned modulator of vast physiological systems. It essentially mediates these physiological effects by interacting with cyclic GMP (cGMP) leading to the regulation of intracellular calcium ions. NO regulates the release of proinflammatory molecules, interacts with ROS leading to the formation of reactive nitrogen species (RNS), and targets vital organelles such as mitochondria, ultimately causing cellular death, a hallmark of many neurodegenerative diseases. AD is an enervating neurodegenerative disorder with an obscure etiology. Because of accumulating experimental data continually highlighting the role of NO in neuroinflammation and AD progression, we explore the most recent data to highlight in detail newly investigated molecular mechanisms in which NO becomes relevant in neuronal inflammation and oxidative stress-associated neurodegeneration in the CNS as well as lay down up-to-date knowledge regarding therapeutic approaches targeting NO.
Journal of Aging Research, 2011
With the demographic shift in age in advanced countries inexorably set to progress in the 21st century, dementia will become one of the most important health problems worldwide. Vascular cognitive impairment is the second most common type of dementia after Alzheimer's disease and is frequently responsible for the cognitive decline of the elderly. It is characterized by cerebrovascular white matter changes; thus, in order to investigate the underlying mechanisms involved in white matter changes, a mouse model of chronic cerebral hypoperfusion has been developed, which involves the narrowing of the bilateral common carotid arteries with newly designed microcoils. The purpose of this paper is to provide a comprehensive summary of the achievements made with the model that shows good reproducibility of the white matter changes characterized by blood-brain barrier disruption, glial activation, oxidative stress, and oligodendrocyte loss following chronic cerebral hypoperfusion. Detailed characterization of this model may help to decipher the substrates associated with impaired memory and move toward a more integrated therapy of vascular cognitive impairment.
Journal of Cerebral Blood Flow & Metabolism, 2005
An aging rat model of chronic brain hypoperfusion (CBH) that mimics human mild cognitive impairment (MCI) was used to examine the role of nitric oxide synthase (NOS) isoforms on spatial memory function. Rats with CBH underwent bilateral common carotid artery occlusion (2-vessel occlusion (2-VO)) for either 26 or 8 weeks and were compared with nonoccluded sham controls (S-VO). The neuronal and endothelial (nNOS/eNOS) constitutive inhibitor nitro-L-arginine methyl ester (L-NAME) 20 mg/kg was administered after 26 weeks for 3 days to 2-VO and S-VO groups and spatial memory was assessed with a modified Morris watermaze test. Only 2-VO rats worsened their spatial memory ability after L-NAME. Electron microscopic immunocytochemical examination using an antibody against eNOS showed 2-VO rats had significant loss or absence of eNOS-containing positive gold particles in hippocampal endothelium and these changes were associated with endothelial cell compression, mitochondrial damage and heavy amyloid deposition in hippocampal capillaries and perivascular region. In the 8-week study, three groups of 2-VO rats were administered an acute dose of 7-NI, aminoguanidine or L-NIO, the relatively selective inhibitors of nNOS, inducible NOS and eNOS. Only rats administered the eNOS inhibitor L-NIO worsened markedly their watermaze performance (P = 0.009) when compared with S-VO nonoccluded controls. We conclude from these findings that vascular nitric oxide derived from eNOS may play a critical role in spatial memory function during CBH possibly by keeping cerebral perfusion optimal through its regulation of microvessel tone and cerebral blood flow and that disruption of this mechanism can result in spatial memory impairment. These findings may identify therapeutic targets for preventing MCI and treating Alzheimer's disease.