Amyloid at the blood vessel wall
University of Sydney, Sydney, New South Wales, Australia Nature Medicine
(Impact Factor: 27.36).
08/2006; 12(7):756-7. DOI: 10.1038/nm0706-756
An APP gene duplication found in French families with beta-amyloidopathy suggests a link between dementia and the vasculature.
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Available from: Beatriz Monteiro Longo
- "vessel disruption, which is induced by Aβ deposition in the vessel walls (Hardy and Cullen, 2006; Zhang-Nunes et al., 2006). In transgenic AD models, the animals exhibit several symptoms similar to those observed in AD patients, including Aβ accumulation in the brain parenchyma and around the blood vessels, as well as significant vascular abnormalities and cognitive and social behavioral deficits. "
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ABSTRACT: Alzheimer´s disease (AD) is clinically characterized by progressive memory loss, behavioural and learning dysfunction and cognitive deficits, such as alterations in social interactions. The major pathological features of AD are the formation of senile plaques and neuroﬁbrillary tangles together with neuronal and vascular damage. The double transgenic mouse model of AD (2xTg-AD) with the APPswe/PS1dE9 mutations shows characteristics that are similar to those observed in AD patients, including social memory impairment, senile plaque formation and vascular deﬁcits. Mesenchymal stem cells (MSCs), when transplanted into the brain, produce positive effects by reducing Aβ deposition in transgenic APP/PS1 mice. Vascular endothelial growth factor (VEGF), exhibits neuroprotective effects against the excitotoxicity implicated in the AD neurodegeneration.The present study investigates the effects of MSCs overexpressing VEGF in hippocampal neovascularization, cognitive dysfunction and senile plaques present in 2xTg-AD transgenic mice. MSC were transfected with uP-VEGF vector, by electroporation and expanded at the 14th passage. 2xTg-AD animals at 6, 9 and 12 months old were transplanted with MSC-VEGF or MSC. The animals were tested for behavioral tasks to access locomotion, novelty exploration, learning and memory, and their brains were analyzed by IHC for vascularization and Aβ plaques. MSC-VEGF treatment favored the neovascularization and diminished senile plaques in hippocampal specific layers. Consequently, the treatment was able to provide behavioral benefits and reduce cognitive deficits by recovering the innate interest to novelty and counteracting memory deficits present in these AD transgenic animals. Therefore, this study has important therapeutic implications for the vascular damage in the neurodegeneration promoted by Alzheimer’s disease.
Available from: Errol Y St A Morrison
- "Oligomerisation represents a major step in the transformation of the monomeric nontoxic peptide to the aggregated neurotoxic form that can account for memory impairment . HDL may also remove Aβ that accumulates in the vessel wall during the course of VD; by analogy with reverse cholesterol transport, such a process can be termed “reverse amyloid transport” . In decreasing oxidative stress, HDL directly decreased Aβ production, as oxidative stress induces enhanced production of Aβ as a potentially protective response . "
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ABSTRACT: High-density lipoprotein (HDL) is one of the major carriers of cholesterol in the blood. It attracts particular attention because, in contrast with other lipoproteins, as many physiological functions of HDL influence the cardiovascular system in favourable ways unless HDL is modified pathologically. The functions of HDL that have recently attracted attention include anti-inflammatory and anti-oxidant activities. High anti-oxidant and anti-inflammatory activities of HDL are associated with protection from cardiovascular disease. Atheroprotective activities, as well as a functional deficiency of HDL, ultimately depend on the protein and lipid composition of HDL. Further, numerous epidemiological studies have shown a protective association between HDL-cholesterol and cognitive impairment. Oxidative stress, including lipid peroxidation, has been shown to be the mediator of the pathologic effects of numerous risk factors of Alzheimer's disease. Lifestyle interventions proven to increase HDL- cholesterol levels including "healthy" diet, regular exercise, weight control, and smoking cessation have also been shown to provide neuro-protective effects. This review will focus on current knowledge of the beneficial effects of HDL-cholesterol as it relates to cardiovascular diseases, breast and lung cancers, non-Hodgkin's lymphoma, as well as its neuroprotective potential in reducing the risk of Alzheimer's disease and dementia.
Available from: Carlos Spuch
- "Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by elevated levels of amyloid beta-peptide (Ab) in the brain, associated with neuronal   and vascular toxicity . Recent investigations emphasize on several aspects of this neurodegenerative disease: co-morbidity of AD and cerebrovascular disease ; AD and atherosclerosis ; cognitive impairment and amyloid angiopathy ; and cerebral microvascular pathology  and deficient clearance of Ab across the bloodebrain barrier (BBB) in AD   . "
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ABSTRACT: Cerebrovascular dysfunction contributes to cognitive decline and neurodegeneration in Alzheimer's disease (AD). Vascular endothelial growth factor (VEGF), an angiogenic protein with important neurotrophic and neuroprotective actions, is under investigation as a therapeutic agent for the treatment of neurodegenerative disorders. The aim of this study was to generate encapsulated VEGF-secreting cells and implant them in a transgenic mouse model of AD, the double mutant amyloid precursor protein/presenilin 1 (APP/Ps1) mice, which shows a disturbed vessel homeostasis. We report that, after implantation of VEGF microcapsules, brain Abeta burden, hyperphosphorylated-tau and cognitive impairment attenuated in APP/Ps1 mice. Based on the neurovascular hypothesis, our findings suggest a new potential therapeutic approach that could be developed for AD, to enhance Abeta clearance and neurovascular repair, and to protect the cognitive behavior. Stereologically-implanted encapsulated VEGF-secreting cells could offer an alternative strategy in the treatment of AD.
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