Neurovascular Dysfunction and Faulty Amyloid  -Peptide Clearance in Alzheimer Disease

Sagare, Abhay P.; Bell, Robert D.; Zloković, Berislav V.

doi:10.1101/cshperspect.a011452

Cited by 215 publications

(189 citation statements)

References 176 publications

(225 reference statements)

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“…138 Reduced A clearance has been described in AD and is associated with reduced cerebral blood flow and impaired cognitive function. 139 Epidemiologic data support an important role for pericytes, as their number and density in the cortex and hippocampus of AD patients was significantly reduced as compared with nondemented controls. 140 Similar observations in A overexpressing mice showed that pericyte deficiency causes an upregulation in A and p-tau expression.…”

Section: Blood-brain Barrier Dysfunctionmentioning

confidence: 99%

The neuropathology and cerebrovascular mechanisms of dementia

Raz

Knoefel

Bhaskar

2015

J Cereb Blood Flow Metab

368

284

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The prevalence of dementia is increasing in our aging population at an alarming rate. Because of the heterogeneity of clinical presentation and complexity of disease neuropathology, dementia classifications remain controversial. Recently, the National Plan to address Alzheimer's Disease prioritized Alzheimer's disease-related dementias to include: Alzheimer's disease, dementia with Lewy bodies, frontotemporal dementia, vascular dementia, and mixed dementias. While each of these dementing conditions has their unique pathologic signature, one common etiology shared among all these conditions is cerebrovascular dysfunction at some point during the disease process. The goal of this comprehensive review is to summarize the current findings in the field and address the important contributions of cerebrovascular, physiologic, and cellular alterations to cognitive impairment in these human dementias. Specifically, evidence will be presented in support of small-vessel disease as an underlying neuropathologic hallmark of various dementias, while controversial findings will also be highlighted. Finally, the molecular mechanisms shared among all dementia types including hypoxia, oxidative stress, mitochondrial bioenergetics, neuroinflammation, neurodegeneration, and bloodbrain barrier permeability responsible for disease etiology and progression will be discussed.

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Section: Blood-brain Barrier Dysfunctionmentioning

confidence: 99%

The neuropathology and cerebrovascular mechanisms of dementia

Raz

Knoefel

Bhaskar

2015

J Cereb Blood Flow Metab

368

284

View full text Add to dashboard Cite

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“…BBB disruption has also been associated with cognitive impairments (28,29). Of note, chronic, but not acute, hypertension increases BBB leakage for small molecules, which causes cognitive impairment by enhancing exposure of angiotensin II to perivascular macrophage (30).…”

Section: Inflammatory Gene Expression and Cognitive Function In Earlymentioning

confidence: 99%

Size-selective opening of the blood–brain barrier by targeting endothelial sphingosine 1–phosphate receptor 1

Yanagida

Liu

Faraco

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

184

162

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The vasculature of the central nervous system (CNS) forms a selective barrier termed the blood-brain barrier (BBB). Disruption of the BBB may contribute to various CNS diseases. Conversely, the intact BBB restricts efficient penetration of CNS-targeted drugs. Here, we report the BBB-regulatory role of endothelial sphingosine 1-phosphate (S1P) receptor-1, a G protein-coupled receptor known to promote the barrier function in peripheral vessels. Endothelial-specific S1pr1 knockout mice (S1pr1 iECKO ) showed BBB breach for small-molecular-mass fluorescence tracers (<3 kDa), but not larger tracers (>10 kDa). Chronic BBB leakiness was associated with cognitive impairment, as assessed by the novel object recognition test, but not signs of brain inflammation. Brain microvessels of S1pr1 iECKO mice showed altered subcellular distribution of tight junctional proteins. Pharmacological inhibition of S1P 1 function led to transient BBB breach. These data suggest that brain endothelial S1P 1 maintain the BBB by regulating the proper localization of tight junction proteins and raise the possibility that endothelial S1P 1 inhibition may be a strategy for transient BBB opening and delivery of small molecules into the CNS.blood-brain barrier | sphingosine 1-phosphate | endothelium | tight junction | drug delivery

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“…The accumulation of different vasculotoxic and neurotoxic macromolecules in the brain as a result of hypoxia and the reduced cerebral blood flow can initiate neuronal dysfunction and neurodegenerative changes regardless of or prior to Aβ deposition. 66 Neurovascular dysfunction as an integral part of AD may influence the onset and progression of cognitive decline and the establishment of a chronic neurodegenerative process.…”

Section: Signs Of Neurodegeneration In Oxys Ratsmentioning

confidence: 99%

Senescence-accelerated OXYS rats: A model of age-related cognitive decline with relevance to abnormalities in Alzheimer disease

et al. 2014

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Senescence-accelerated OXYS rats are an experimental model of accelerated aging that was established from wistar stock via selection for susceptibility to cataractogenic effects of a galactose-rich diet and via subsequent inbreeding of highly susceptible rats. Currently, we have the 102nd generation of OXYS rats with spontaneously developing cataract and accelerated senescence syndrome, which means early development of a phenotype similar to human geriatric disorders, including accelerated brain aging. in recent years, our group found strong evidence that OXYS rats are a promising model for studies of the mechanisms of brain aging and neurodegenerative processes similar to those seen in Alzheimer disease (AD). The manifestation of behavioral alterations and learning and memory deficits develop since the fourth week of age, i.e., simultaneously with first signs of neurodegeneration detectable on magnetic resonance imaging and under a light microscope. in addition, impaired long-term potentiation has been demonstrated in OXYS rats by the age of 3 months. with age, neurodegenerative changes in the brain of OXYS rats become amplified. we have shown that this deterioration happens against the background of overproduction of amyloid precursor protein (AβPP), accumulation of β-amyloid (Aβ), and hyperphosphorylation of the tau protein in the hippocampus and cortex. The development of AMDlike retinopathy in OXYS rats is also accompanied by increased accumulation of Aβ in the retina. These published data suggest that the OXYS strain may serve as a spontaneous rat model of AD-like pathology and could help to decipher the pathogenesis of AD.

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Neurovascular Dysfunction and Faulty Amyloid -Peptide Clearance in Alzheimer Disease

Cited by 215 publications

References 176 publications

The neuropathology and cerebrovascular mechanisms of dementia

The neuropathology and cerebrovascular mechanisms of dementia

Size-selective opening of the blood–brain barrier by targeting endothelial sphingosine 1–phosphate receptor 1

Senescence-accelerated OXYS rats: A model of age-related cognitive decline with relevance to abnormalities in Alzheimer disease

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