Depletion of Vitamin E Increases Amyloid β Accumulation by Decreasing Its Clearances from Brain and Blood in a Mouse Model of Alzheimer Disease

Nishida, Yoichiro; Ito, Shingo; Ohtsuki, Sumio; Yamamoto, Naoki; Takahashi, Tsubura; Iwata, Nobuhisa; Jishage, Kou Ichi; Yamada, Hiromi; Sasaguri, Hiroki; Yokota, Shigefumi; Piao, Wenying; Tomimitsu, Hiroyuki; Saido, Takaomi C.; Yanagisawa, Katsuhiko; Terasaki, Tetsuya; Mizusawa, Hidehiro; Yokota, Takanori

doi:10.1074/jbc.m109.054056

Cited by 97 publications

(59 citation statements)

References 44 publications

(49 reference statements)

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“…In AD mouse models, the expression levels of neprilysin and IDE in microglia were decreased in 14-month-old mice (Hickman et al, 2008). Recent studies demonstrated that IDE expression and activity were complexly regulated by various factors, including aging, Apo E, cytokines, and vitamin E (Eckman and Eckman, 2005;Jiang et al, 2008;Shimizu et al, 2008;Nishida et al, 2009). Therefore, the upregulation of IDE represents a promising strategy for therapy and prevention for AD.…”

Section: Discussionmentioning

confidence: 99%

Norepinephrine Promotes Microglia to Uptake and Degrade Amyloid β Peptide through Upregulation of Mouse Formyl Peptide Receptor 2 and Induction of Insulin-Degrading Enzyme

Kong

Ruan²,

Qian³

et al. 2010

J. Neurosci.

109

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Locus ceruleus (LC) is the main subcortical site of norepinephrine synthesis. In Alzheimer's disease (AD) patients and rodent models, degeneration of LC neurons and reduced levels of norepinephrine in LC projection areas are significantly correlated with the increase in amyloid plaques, neurofibrillary tangles, and severity of dementia. Activated microglia play a pivotal role in the progression of AD by either clearing amyloid ␤ peptide (A␤) deposits through uptake of A␤ or releasing cytotoxic substances and proinflammatory cytokines. Here, we investigated the effect of norepinephrine on A␤ uptake and clearance by murine microglia and explored the underlying mechanisms. We found that murine microglia cell line N9 and primary microglia expressed ␤ 2 adrenergic receptor (AR) but not ␤ 1 and ␤ 3 AR. Norepinephrine and isoproterenol upregulated the expression of A␤ receptor mFPR2, a mouse homolog of human formyl peptide receptor FPR2, through activation of ␤ 2 AR in microglia. Norepinephrine also induced mFPR2 expression in mouse brain. Activation of ␤ 2 AR in microglia promoted A␤ 42 uptake through upregulation of mFPR2 and enhanced spontaneous cell migration but had no effect on cell migration in response to mFPR2 agonists. Furthermore, activation of ␤ 2 AR on microglia induced the expression of insulin-degrading enzyme and increased the degradation of A␤ 42 . Mechanistic studies showed that isoproterenol induced mFPR2 expression through ERK1/2-NF-B and p38-NF-B signaling pathways. These findings suggest that noradrenergic innervation from LC is needed to maintain adequate A␤ uptake and clearance by microglia, and norepinephrine is a link between neuron and microglia to orchestrate the host response to A␤ in AD.

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Section: Discussionmentioning

confidence: 99%

Norepinephrine Promotes Microglia to Uptake and Degrade Amyloid β Peptide through Upregulation of Mouse Formyl Peptide Receptor 2 and Induction of Insulin-Degrading Enzyme

Kong

Ruan²,

Qian³

et al. 2010

J. Neurosci.

109

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“…98,196 In a mouse lacking the antioxidant vitamin E, LRP-1-dependent brain efflux and systemic clearance of Ab are impaired. 197 Both LRP-1 and Pgp are functionally downregulated in the BBB in mice with systemic inflammation induced by LPS, 66,198 and this corresponds with impaired Ab efflux. 66,198 In contrast to AD, decreased function of these transporters after LPS was not attributed to reduced protein levels or oxidative damage.…”

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

459

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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“…One of the mechanisms in removing Aβ is mediated by liver and low-density lipoprotein receptorrelated protein (LRP-1) [8,9]. LRP-1 is a receptor for uptaking Aβ through hepatic [10]. Another mechanism that provokes clearance of Aβ is accumulation of microglia.…”

Section: Introductionmentioning

confidence: 99%

Clearance of Amyloid Beta Plaques from Brain of Alzheimeric Rats by Lavandula angustifolia

Soheili¹,

Tavirani²,

Saifeddine³

2012

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An important marker in neurodegenerative Alzheimer's disease (AD) is abnormal production of amyloid beta (Aβ) peptide leading to formation of plaques in the brain. Through decreasing Aβ aggregates, anti-inflammatory agents, phagocytosis, and proteolytic enzymes are known to decline risk of Aβ plaque formation. In the previous study we showed that aqueous extract of Lavandula angustifolia (lavender), with known anti-inflammatory effects, improves memory deficits in animal model of Alzheimer. Here, we assess if lavender play a role in clearance of Aβ plaques in the hippocampus. The Alzheimeric animals were created with intracerebroventricular injection of Aβ 1-42. To confirm formation of Aβ plaques, brain sections were stained by Congo red method. Twenty days post-injection they were administered with different doses (50, 100 and 200 mg/kg) of the aqueous extract of lavender for duration of 20 days. Our results demonstrated that 50 mg/kg of lavender not effectively influenced the Aβ plaques. On the other hand, the herbal medicine at the doses of 100 and 200 mg/kg markedly decreased the extent of Aβ aggregates. We concluded that the lavender extract dose dependently underlies elimination of Aβ plaques. The exact mechanism by which the herbal medicine removes the Aβ aggregates needs to be elucidated.

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Depletion of Vitamin E Increases Amyloid β Accumulation by Decreasing Its Clearances from Brain and Blood in a Mouse Model of Alzheimer Disease

Cited by 97 publications

References 44 publications

Norepinephrine Promotes Microglia to Uptake and Degrade Amyloid β Peptide through Upregulation of Mouse Formyl Peptide Receptor 2 and Induction of Insulin-Degrading Enzyme

Norepinephrine Promotes Microglia to Uptake and Degrade Amyloid β Peptide through Upregulation of Mouse Formyl Peptide Receptor 2 and Induction of Insulin-Degrading Enzyme

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

Clearance of Amyloid Beta Plaques from Brain of Alzheimeric Rats by Lavandula angustifolia

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