Interaction Between a Rat Model of Cerebral Ischemia and β-Amyloid Toxicity

Whitehead, Shawn N.; Hachinski, Vladimir; Cechetto, David F.

doi:10.1161/01.str.0000149627.30763.f9

Cited by 81 publications

(83 citation statements)

References 23 publications

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“…Clinical data clearly indicate that the coexistence of stroke and Alzheimer disease (AD) leads to exacerbated dementia, 3 and experimental studies with animals have addressed the relationship between stroke and AD. [4][5][6][7][8][9] Although human studies have also indicated that soluble parenchymal amyloid precursor protein and β-amyloid 1 to 42 (Aβ 1-42 ) accumulate in patients with multi-infarct dementia, 10,11 there are animal studies examining neurodegenerative mechanisms and cognitive impairment in global and focal experimental ischemia.…”

Section: Evidence From Experimental Studiesmentioning

confidence: 99%

Amyloid Burden, Neuroinflammation, and Links to Cognitive Decline After Ischemic Stroke

Thiel

Cechetto

Heiss

et al. 2014

Stroke

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110

102

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O ne in 5 patients with stroke will end up demented shortly after a stroke, half with prior cognitive impairment and half without. After recurrent stroke, more than a third will become demented. 1 The mechanisms remain unclear beyond the fact that neurodegenerative and vascular mechanisms contribute to the cognitive decline.2 In this review, we explore experimental and clinical evidence of interaction between ischemia, amyloid deposition, and neuroinflammation and identify new potential therapeutic targets. Evidence From Experimental StudiesClinical data clearly indicate that the coexistence of stroke and Alzheimer disease (AD) leads to exacerbated dementia, 3 and experimental studies with animals have addressed the relationship between stroke and AD. [4][5][6][7][8][9] Although human studies have also indicated that soluble parenchymal amyloid precursor protein and β-amyloid 1 to 42 (Aβ 1-42 ) accumulate in patients with multi-infarct dementia, 10,11 there are animal studies examining neurodegenerative mechanisms and cognitive impairment in global and focal experimental ischemia. Changes in neurotransmitter systems, trophic factors, and cell signaling and neuroinflammatory mechanisms have been well documented.12 Experimental animal models of cognitive impairment have demonstrated the presence of amyloid precursor protein in the area of ischemic damage.13 Studies in mice overexpressing mutated presenilin 1 or presenilinknockout mice suggest that presenilin 1 mutations lead to enhanced neurodegeneration after focal ischemia or excitotoxicity. 9,14 This may suggest that mutations leading to higher levels of Aβ may increase the sensitivity to ischemia. In another study, mice overexpressing amyloid precursor protein with middle cerebral artery occlusion were shown to have enlarged infarcts and a stronger reduction of blood flow after the arterial occlusion.15 These experiments, however, also showed that the vasodilatory effect of the endothelium-dependent vasodilator acetylcholine was significantly reduced in transgenic mice, possibly suggesting that Aβ-induced disturbance in endothelium-dependent vascular reactivity may contribute to the higher ischemia sensitivity. Our research group has conducted several studies directly examining the pathological, neuroinflammatory, and behavioral relationship of stroke and AD in rat and mouse models. [4][5][6][7] In particular, these studies have focused on the potential synergism that would account for the clinical findings. A consequence of a chronic neuroinflammatory response is perturbation of the cerebrovascular system. Likewise, a perturbation of the cerebrovascular system will influence the degree of neuroinflammation after injury. A considerable body of evidence has demonstrated that AD is directly related to and has profound pathological changes in the cerebral microvasculature.16 Specific attention has recently focused on changes within brain endothelial cells in AD and in response to exposure to Aβ. 16 It has been hypothesized that during the onset of AD the breakdow...

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Section: Evidence From Experimental Studiesmentioning

confidence: 99%

Amyloid Burden, Neuroinflammation, and Links to Cognitive Decline After Ischemic Stroke

Thiel

Cechetto

Heiss

et al. 2014

Stroke

Self Cite

110

102

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“…[21][22][23]33 Further, microglial or astroglial activation in the hippocampus has been reported in animal models of chronic cerebral hypoperfusion or A␤ toxicity. 20,21 A rat model with a combined injury of lacunar infarction and A␤ toxicity showed increased neuroinflammation in the hippocampus. 20 In our experiment, neuroinflammation was increased by the permanent occlusion of bilateral common carotid arteries and A␤ toxicity, as compared to that in sham-operated rats; however, an additional synergistic exacerbating effect was not definite in the combined injury group.…”

mentioning

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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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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“…A number of prior models of subcortical stroke have been described including focal injections of endothelin-1 into the internal capsule, subcortical white matter and striatum in the rat [12][13][14] and mouse 6,15 . More recent models of small focal strokes have utilized cholesterol microemboli injection in the carotid artery 16 and photothrombotic occlusion of a single penetrating arteriole 17 .…”

Section: Discussionmentioning

confidence: 99%

A Versatile Murine Model of Subcortical White Matter Stroke for the Study of Axonal Degeneration and White Matter Neurobiology

Nunez

Doroudchi

Gleichman

et al. 2016

JoVE

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Stroke affecting white matter accounts for up to 25% of clinical stroke presentations, occurs silently at rates that may be 5-10 fold greater, and contributes significantly to the development of vascular dementia. Few models of focal white matter stroke exist and this lack of appropriate models has hampered understanding of the neurobiologic mechanisms involved in injury response and repair after this type of stroke. The main limitation of other subcortical stroke models is that they do not focally restrict the infarct to the white matter or have primarily been validated in non-murine species. This limits the ability to apply the wide variety of murine research tools to study the neurobiology of white matter stroke. Here we present a methodology for the reliable production of a focal stroke in murine white matter using a local injection of an irreversible eNOS inhibitor. We also present several variations on the general protocol including two unique stereotactic variations, retrograde neuronal tracing, as well as fresh tissue labeling and dissection that greatly expand the potential applications of this technique. These variations allow for multiple approaches to analyze the neurobiologic effects of this common and understudied form of stroke. Video LinkThe video component of this article can be found at

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Interaction Between a Rat Model of Cerebral Ischemia and β-Amyloid Toxicity

Cited by 81 publications

References 23 publications

Amyloid Burden, Neuroinflammation, and Links to Cognitive Decline After Ischemic Stroke

Amyloid Burden, Neuroinflammation, and Links to Cognitive Decline After Ischemic Stroke

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

A Versatile Murine Model of Subcortical White Matter Stroke for the Study of Axonal Degeneration and White Matter Neurobiology

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