Alzheimer's Disease, Cerebrovascular Disease, and the β-amyloid Cascade

Honjo, Kazuhito; Black, Sandra E.; Verhoeff, Nicolaas Paul L.G.

doi:10.1017/s0317167100015547

Cited by 146 publications

(106 citation statements)

References 210 publications

(281 reference statements)

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“…235 Ischemia caused by cerebrovascular disease can cause Ab accumulation, inflammation, and oxidative stress in the CNS that trigger BBB dysfunction. 236 In a rodent model of brain ischemia induced by microsphere embolism, microvascular accumulation of Ab occurs and coincides with parenchymal Ab deposition and tau hyperphosphorylation. 237 This raises the question of whether vascular pathologies themselves contribute to AD.…”

Section: Alzheimer's Disease Risk Factors and The Blood-brain Barriermentioning

confidence: 99%

Blood–Brain Barrier Dysfunction as a Cause and Consequence of Alzheimer's Disease

Erickson

Banks

2013

J Cereb Blood Flow Metab

458

363

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The blood-brain barrier (BBB) plays critical roles in the maintenance of central nervous system (CNS) homeostasis. Dysfunction of the BBB occurs in a number of CNS diseases, including Alzheimer's disease (AD). A prevailing hypothesis in the AD field is the amyloid cascade hypothesis that states that amyloid-b (Ab) deposition in the CNS initiates a cascade of molecular events that cause neurodegeneration, leading to AD onset and progression. In this review, the participation of the BBB in the amyloid cascade and in other mechanisms of AD neurodegeneration will be discussed. We will specifically focus on three aspects of BBB dysfunction: disruption, perturbation of transporters, and secretion of neurotoxic substances by the BBB. We will also discuss the interaction of the BBB with components of the neurovascular unit in relation to AD and the potential contribution of AD risk factors to aspects of BBB dysfunction. From the results discussed herein, we conclude that BBB dysfunction contributes to AD through a number of mechanisms that could be initiated in the presence or absence of Ab pathology. Keywords: Alzheimer's disease; blood-brain barrier; cerebrospinal fluid; diabetes; inflammation; neurovascular unit INTRODUCTION Alzheimer's disease (AD) is the most common type of dementia, and affects B36 million individuals worldwide (http://www.alz. co.uk/research/world-report). The majority of individuals afflicted with AD initially present with symptoms of memory loss and cognitive impairment late in life (Z65 years old). These symptoms increase in severity as AD progresses, often become so debilitating that institutionalization is necessary, and are eventually fatal. Therefore, AD is a disease with tremendous socioeconomic cost. Because of the growing aged population and lack of treatments that can prevent or slow disease progression, future AD prevalence is expected to increase to an extent that it may threaten the sustainability of healthcare systems worldwide. This necessitates a global effort to better understand AD, with the goal of developing treatments that can prevent or slow AD progression. Journal of Cerebral BloodMuch of the focus in AD research has been on amyloid-b peptide (Ab) and tau, which are the protein constituents of the hallmark senile plaques and neurofibrillary tangles that pathologically define AD. The amyloid cascade hypothesis, initially proposed by Hardy and Higgins in 1992, 1 updated by Hardy and Selkoe in 2002, 2 and still a prevalent focus of AD research today, states that deposition of Ab in the brain is the initiating event in AD. Although the hypothesis remains generally accepted, it is also increasingly evident that Ab plays a complex, multifaceted role in AD progression. In rare, familial forms of AD, mutations in the Ab precursor protein (APP) or in presenilin proteins, the enzymes that cleave Ab from APP, cause increased Ab deposition. In the remainder of AD cases, it is thought that Ab deposition results from deficient clearance. 2 Multiple routes of clearance have been elucidat...

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Section: Alzheimer's Disease Risk Factors and The Blood-brain Barriermentioning

confidence: 99%

Blood–Brain Barrier Dysfunction as a Cause and Consequence of Alzheimer's Disease

Erickson

Banks

2013

J Cereb Blood Flow Metab

458

363

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“…Alzheimer's disease (AD), the most common form of dementia, is characterized by the progressive loss of neurons and synapses, and by extracellular deposits of Aβ in the form of senile plaques, A deposits in the cerebral blood vessels, and intracellular inclusions of hyperphosphorylated tau in the form of neurofibrillary tangles (NFT) [348,349]. Several mechanisms contribute to AD development and progression, and deposition of improperly processed amyloid is thought to be a major factor in its pathophysiology.…”

Section: C) Alzheimer's Diseasementioning

confidence: 99%

Metalloproteinases and Metalloproteinase Inhibitors in Age-Related Diseases

Gargiulo¹,

Gamba²,

Poli³

et al. 2014

CPD

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Degradation of the extracellular matrix is an important feature of embryonic development, morphogenesis, angiogenesis, tissue repair and remodeling. It is precisely regulated under physiological conditions, but when dysregulated it becomes a cause of many diseases, including atherosclerosis, osteoarthritis, diabetic vascular complications, and neurodegeneration. Various types of proteinases are implicated in extracellular matrix degradation, but the major enzymes are considered to be metalloproteinases such as matrix metalloproteinases (MMPs) and disintegrin and metalloproteinase domain (ADAMs) that include ADAMs with a thrombospondin domain (ADAMTS).This review discusses involvement of the major metalloproteinases in some age-related chronic diseases, and examines what is currently known about the beneficial effects of their inhibitors, used as new therapeutic strategies for treating or preventing the development and progression of these diseases.

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“…It has been noticed for decades that cerebral amyloid angiopathy in AD induces a severe form of cerebrovascular dysfunction, leading to intra-and postischemic cerebral blood flow deficits that ultimately exacerbate cerebral infarction [17]. Brain infarcts by themselves had little effect on cognitive status [18]; however, infarcts as well as vascular risk factors and cerebrovascular disease may accelerate Aβ production/aggregation/deposition and contribute to the pathology and symptomatology of AD [19]. For these reasons, flavonoid compounds may introduce changes in cerebrovascular blood flow and therefore promote angiogenesis, neurogenesis, and alterations in neuronal morphology, which may finally be beneficial for the improvement of cognitive function in patients with VaD.…”

mentioning

confidence: 99%

The effect of <italic>Scutellaria baicalensis</italic> stem-leaf flavonoids on spatial learning and memory in chronic cerebral ischemia-induced vascular dementia of rats

Cao¹,

Liu²,

Xu³

et al. 2016

ABBS

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Flavonoids have been shown to improve cognitive function and delay the dementia progression. However, the underlying mechanisms remain elusive. In the present study, we examined the effect of Scutellaria baicalensis stem-leaf total flavonoids (SSTFs) extracted from S. baicalensis Georgi on spatial learning and memory in a vascular dementia (VaD) rat model and explored its molecular mechanisms. The VaD rats were developed by permanent bilateral occlusion of the common carotid artery. Seven days after recovery, the VaD rats were treated with either 50 or 100 mg/kg of SSTF for 60 days. The spatial learning and memory was evaluated in the Morris water maze (MWM) test. The tau hyperphosphorylation and the levels of the related protein kinases or phosphatases were examined by western blot analysis. In VaD rats, SSTF treatment at 100 mg/kg significantly reduced the escape latency in training trial in MWM test. In the probe trial, SSTF treatment increased the searching time and travel distance in the target quadrant. SSTF treatment inhibited the tau phosphorylation in both cortex and hippocampus in VaD rats. Meanwhile, SSTF reduced the activity of glycogen synthase kinase 3β and cyclin-dependent kinase 5 in VaD rats. In contrast, SSTF treatment increased the level of the protein phosphatase 2A subunit B in VaD rats. SSTF treatment significantly improved the spatial cognition in VaD rats. Our results suggest that SSTF may alleviate tauhyperphosphorylation-induced neurotoxicity through coordinating the activity of kinases and phosphatase after a stroke. SSTF may be developed into promising novel therapeutics for VaD.

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Alzheimer's Disease, Cerebrovascular Disease, and the β-amyloid Cascade

Cited by 146 publications

References 210 publications

Blood–Brain Barrier Dysfunction as a Cause and Consequence of Alzheimer's Disease

Blood–Brain Barrier Dysfunction as a Cause and Consequence of Alzheimer's Disease

Metalloproteinases and Metalloproteinase Inhibitors in Age-Related Diseases

The effect of <italic>Scutellaria baicalensis</italic> stem-leaf flavonoids on spatial learning and memory in chronic cerebral ischemia-induced vascular dementia of rats

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Alzheimer's Disease, Cerebrovascular Disease, and the β-amyloid Cascade

Cited by 146 publications

References 210 publications

Blood–Brain Barrier Dysfunction as a Cause and Consequence of Alzheimer's Disease

Blood–Brain Barrier Dysfunction as a Cause and Consequence of Alzheimer's Disease

Metalloproteinases and Metalloproteinase Inhibitors in Age-Related Diseases

The effect of &lt;italic&gt;Scutellaria baicalensis&lt;/italic&gt; stem-leaf flavonoids on spatial learning and memory in chronic cerebral ischemia-induced vascular dementia of rats

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The effect of <italic>Scutellaria baicalensis</italic> stem-leaf flavonoids on spatial learning and memory in chronic cerebral ischemia-induced vascular dementia of rats