Are Alzheimer’s disease, hypertension, and cerebrocapillary damage related?☆

Farkas, Eszter; Vos, Rob A. I. de; Steur, Ernst N.H. Jansen; Luiten, P.G.M.

doi:10.1016/s0197-4580(00)00122-6

Cited by 48 publications

(27 citation statements)

References 51 publications

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“…15,40,41 Further, permanent occlusion of bilateral common carotid arteries-induced suboptimal cerebral perfusion may generate ultrastructural damage of the cerebral capillary walls. 13 In our experiment, this capillary damage may have had some effect on the normal clearance of AD-related pathology. However, no definite morphological changes of the vascular basement membranes in the capillaries were observed.…”

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confidence: 59%

“…4 The Rotterdam study, 9 a large population-based prospective study, reported an increased prevalence of atherosclerosis in patients either with AD or Received March 11, 2011; accepted March 31, 2011 A converging hypothesis involving chronic cerebral hypoperfusion and AD pathology originally has been suggested in clinical studies. [11][12][13] Furthermore, the double-hit vascular hypothesis of AD, based on molecular and cellular experimental studies, has been proposed. 14 -17 An intact functional neurovascular unit is an active system prerequisite to maintain normal brain function.…”

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confidence: 99%

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Synergistic Memory Impairment Through the Interaction of Chronic Cerebral Hypoperfusion and Amlyloid Toxicity in a Rat Model

Choi

Lee²,

Han³

et al. 2011

Stroke

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Background and Purpose-Vascular pathology and Alzheimer disease (AD) pathology have been shown to coexist in the brains of dementia patients. We investigated how cognitive impairment could be exacerbated in a rat model of combined injury through the interaction of chronic cerebral hypoperfusion and amyloid beta (A␤) toxicity. Methods-In Wistar rats, chronic cerebral hypoperfusion was modeled by permanent occlusion of bilateral common carotid arteries (BCCAo). Further, AD pathology was modeled by bilateral intracerebroventricular A␤ (A␤ toxicity) using a nonphysiological A␤ peptide (A␤ 25 to 35). The experimental animals were divided into 4 groups, including sham, single injury (A␤ toxicity or BCCAo), and combined injury (BCCAo-A␤ toxicity) groups (nϭ7 per group) . Cerebral blood flow and metabolism were measured using small animal positron emission tomography. A Morris water maze task, novel object location and recognition tests, and histological investigation, including neuronal cell death, apoptosis, neuroinflammation, and AD-related pathology, were performed. Results-Spatial memory impairment was synergistically exacerbated in the BCCAo-A␤ toxicity group as compared to the BCCAo or A␤ toxicity groups (PϽ0.05). Compared to the sham group, neuroinflammation with microglial or astroglial activation was increased both in multiple white matter lesions and the hippocampus in other experimental groups. AD-related pathology was enhanced in the BCCAo-A␤ toxicity group compared to the A␤ toxicity group. Conclusion-Our experimental results support a clinical hypothesis of the deleterious interaction between chronic cerebralhypoperfusion and A␤ toxicity. Chronic cerebral hypoperfusion-induced perturbation in the equilibrium of AD-related pathology may exacerbate cognitive impairment in a rat model of combined injury. (Stroke. 2011;42:2595-2604.)Key Words: Alzheimer disease Ⅲ amyloid beta Ⅲ chronic cerebral hypoperfusion Ⅲ Morris water maze Ⅲ vascular dementia A lzheimer disease (AD) and vascular dementia are the most common causes of cognitive decline in the aging population. 1 Accumulation of insoluble amyloid beta (A␤) in the brain has been identified as the major culprit for the cognitive impairment observed in AD patients. 2 Because senile plaques composed of the A␤ peptide have been found in the brains of AD patients, 2 extensive research has focused on the amyloid hypothesis to explain AD pathology.A hypothesis emphasizing the interaction between AD and vascular pathologies has recently emerged. [3][4][5] The Nun study and other clinico-pathological studies 6 -8 have revealed that patients with AD exhibit concomitant vascular lesions in the brain. Further, epidemiological studies have shown that the major risk factors for AD mostly coincide with those for vascular dementia. 4 The Rotterdam study, 9 a large population-based prospective study, reported an increased prevalence of atherosclerosis in patients either with AD or Received March 11, 2011; accepted March 31, 2011 A converging hypothesis involving chronic ...

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confidence: 99%

Synergistic Memory Impairment Through the Interaction of Chronic Cerebral Hypoperfusion and Amlyloid Toxicity in a Rat Model

Choi

Lee²,

Han³

et al. 2011

Stroke

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“…It is rational, that vascular risk factors may increase the prevalence of AD [17]. In addition, hypertension and microvascular pathology, may be responsible for the subcortical white matter lesions found frequently in AD [3,18,19]. The histopathological and ultrastructural alterations of the vessels in AD [20][21][22], may contribute to the failure of hemodynamic control in crucial for cognition areas of the brain [22,23].…”

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confidence: 99%

The vascular factor in Alzheimer's disease: A study in Golgi technique and electron microscopy

Baloyannis¹,

Baloyannis²

2012

Journal of the Neurological Sciences

130

122

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“…17 However, accurate behavioral assessment of this rat model is often hampered by loss of the visual pathway caused by occlusion of the ophthalmic arteries. Therefore, in the present study, we used a mouse model of cognitive impairment, produced by bilateral common carotid arterial stenosis (BCAS) with microcoils.…”

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confidence: 99%

Apoptosis Signal–Regulating Kinase 1 Is a Novel Target Molecule for Cognitive Impairment Induced by Chronic Cerebral Hypoperfusion

Toyama

Koibuchi

Uekawa

et al. 2014

ATVB

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of VaD and the development of a clinical therapeutic strategy for VaD are urgent topics for research.Apoptosis signal-regulating kinase 1 (ASK1), a member of the mitogen-activated protein (MAP) kinase kinase kinase family, activates MAP kinase kinases, which in turn activate p38 and C-Jun N-terminal (JNK) MAP kinase. Objective-There are currently no specific strategies for the treatment or prevention of vascular dementia. White matter lesions, a common pathology in cerebral small vessel disease, are a major cause of vascular dementia. We investigated whether apoptosis signal-regulating kinase 1 (ASK1) might be a key molecule in cerebral hypoperfusion, associated with blood-brain barrier breakdown and white matter lesions. Approach and Results-A mouse model of cognitive impairment was developed by inducing chronic cerebral hypoperfusion in white matter including the corpus callosum via bilateral common carotid artery stenosis (BCAS) surgery. BCASinduced white matter lesions caused cognitive decline in C57BL/6J (wild-type) mice but not in ASK1-deficient (ASK1 −/− ) mice. Phosphorylated ASK1 increased in wild-type mouse brains, and phosphorylated p38 and tumor necrosis factor-α expression increased in corpus callosum cerebral endothelial cells after BCAS in wild-type mice but not in ASK1 −/− mice. BCAS decreased claudin-5 expression and disrupted blood-brain barrier in the corpus callosum of wild-type but not ASK1 −/− mice. Cerebral nitrotyrosine was increased in wild-type and ASK1 −/− BCAS mice. Cerebral phosphorylated ASK1 did not increase in wild-type mice treated with NADPH-oxidase inhibitor. A p38 inhibitor and NADPH-oxidase inhibitor mimicked the protective effect of ASK1 deficiency against cognitive impairment. Specific ASK1 inhibitor prevented cognitive decline in BCAS mice. In vitro oxygen-glucose deprivation and tumor necrosis factor-α stimulation caused the disruption of endothelial tight junctions from wild-type mice but not ASK1 −/− mice. Conclusions-Oxidative stress-ASK1-p38 cascade plays a role in the pathogenesis of cognitive impairment, through bloodbrain barrier breakdown via the disruption of endothelial tight junctions. ASK1 might be a promising therapeutic target for chronic cerebral hypoperfusion-induced cognitive impairment. Figure I in the online-only Data Supplement). Our previous reports showed that ASK1 is involved in angiotensin II-induced vascular endothelial dysfunction and apoptosis, 10 balloon injury-induced vascular neointima formation, 11 and ischemia-induced angiogenesis. 12The potential role of ASK1 in cerebral vasculature/small vessels should be further investigated in relation to VaD. Cerebral ischemia increases cerebral oxidative stress levels 13 and vascular cognitive impairment induced by chronic cerebral ischemia is associated with BBB disruption.14-16 The BBB consists of endothelial cells, basal lamina matrix, astrocyte end-feet, and pericytes. Therefore, in the present study, we hypothesized that ASK1 might be involved in oxidative stress-induced BBB disruption because ...

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Are Alzheimer’s disease, hypertension, and cerebrocapillary damage related?☆

Cited by 48 publications

References 51 publications

Synergistic Memory Impairment Through the Interaction of Chronic Cerebral Hypoperfusion and Amlyloid Toxicity in a Rat Model

Synergistic Memory Impairment Through the Interaction of Chronic Cerebral Hypoperfusion and Amlyloid Toxicity in a Rat Model

The vascular factor in Alzheimer's disease: A study in Golgi technique and electron microscopy

Apoptosis Signal–Regulating Kinase 1 Is a Novel Target Molecule for Cognitive Impairment Induced by Chronic Cerebral Hypoperfusion

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