Glycoprotein 330/megalin: probable role in receptor-mediated transport of apolipoprotein J alone and in a complex with Alzheimer disease amyloid beta at the blood-brain and blood-cerebrospinal fluid barriers.

Zloković, Berislav V.; Martel, Céline; Matsubara, Etsuro; McComb, J. Gordon; Zheng, Gang; McCluskey, Robert T.; Frangione, Blas; Ghiso, Jorge

doi:10.1073/pnas.93.9.4229

Cited by 391 publications

(323 citation statements)

References 38 publications

(42 reference statements)

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“…LRP2 binds leptin to mediate leptin reuptake in renal tubules and to promote leptin transport across the choroid plexus [21][22][23] , suggesting a molecular link between LRP2 and leptin. LRP2 was also identified as an endocytic receptor for clusterin 24,25 and our preliminary data confirmed the mRNA expression of LRP2 in rodent hypothalamus. In this study we investigated the potential roles for hypothalamic clusterin and LRP2 in the regulation of energy homeostasis.…”

supporting

confidence: 71%

Clusterin and LRP2 are critical components of the hypothalamic feeding regulatory pathway

et al. 2013

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Hypothalamic feeding circuits are essential for the maintenance of energy balance. There have been intensive efforts to discover new biological molecules involved in these pathways. Here we report that central administration of clusterin, also called apolipoprotein J, causes anorexia, weight loss and activation of hypothalamic signal transduction-activated transcript-3 in mice. In contrast, inhibition of hypothalamic clusterin action results in increased food intake and body weight, leading to adiposity. These effects are likely mediated through the mutual actions of the low-density lipoprotein receptor-related protein-2, a potential receptor for clusterin, and the long-form leptin receptor. In response to clusterin, the low-density lipoprotein receptor-related protein-2 binding to long-form leptin receptor is greatly enhanced in cultured neuronal cells. Furthermore, long-form leptin receptor deficiency or hypothalamic low-density lipoprotein receptor-related protein-2 suppression in mice leads to impaired hypothalamic clusterin signalling and actions. Our study identifies the hypothalamic clusterin-low-density lipoprotein receptor-related protein-2 axis as a novel anorexigenic signalling pathway that is tightly coupled with long-form leptin receptor-mediated signalling.

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supporting

confidence: 71%

Clusterin and LRP2 are critical components of the hypothalamic feeding regulatory pathway

et al. 2013

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“…[122][123][124] A recent study measured the efflux, within a 30 min time period, of Ab40/42, apoE and apoJ at BBB in mice. 122 Although the authors found that Ab40 and Ab42 was cleared from ISF within the 30 min, the rate of Ab40 transport across BBB was approximately double that of Ab42.…”

Section: Apolipoprotein J-mediated Transport Of Ab Across Bbbmentioning

confidence: 99%

Clearance mechanisms of Alzheimer's amyloid-β peptide: implications for therapeutic design and diagnostic tests

et al. 2008

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Currently, the 'amyloid hypothesis' is the most widely accepted explanation for the pathogenesis of Alzheimer's disease (AD). According to this hypothesis, altered metabolism of the amyloid-b (Ab) peptide is central to the pathological cascade involved in the pathogenesis of AD. Although Ab is produced by almost every cell in the body, a physiological function for the peptide has not been determined, and the pathways by which Ab leads to cognitive dysfunction and cell death are unclear. Numerous therapeutic approaches that target the production, toxicity and removal of Ab are being developed worldwide. Although therapeutic treatment for AD may be imminent, the value and effectiveness of such treatment are largely dependent on early diagnosis of the disease. This review summarizes current knowledge of Ab clearance, transport and degradation, and evaluates the use of such information in the development of diagnostic tools. The conflicting results of plasma Ab ELISAs are discussed, as are the more promising results of Ab imaging by positron emission tomography. Current knowledge of Ab-binding proteins and Ab-degrading enzymes is analysed in the context of a potential therapy for AD. Transport across the blood-brain barrier by the receptor for advanced glycation end products and efflux via the multi-ligand lipoprotein receptor LRP-1 is also reviewed. Enhancing clearance and degradation of Ab remains an attractive therapeutic strategy, and improved understanding of Ab clearance may lead to advances in diagnostics and interventions designed to prevent or delay the onset of AD.

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“…Choroid plexus epithelial cells show saturable uptake and complete transcytosis of Ab that favors efflux in the CSF-to-blood direction. 135 The BCSFB, like the BBB, expresses transporters for Ab that include LRP-1, 136 LRP-2/megalin, 137 Pgp, 138 and RAGE. 139 The efflux transporters LRP-1 and Pgp in the CP increase with aging, 139 which is opposite to expression patterns observed with aging in the BBB.…”

mentioning

confidence: 99%

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

Erickson

Banks

2013

J Cereb Blood Flow Metab

447

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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Glycoprotein 330/megalin: probable role in receptor-mediated transport of apolipoprotein J alone and in a complex with Alzheimer disease amyloid beta at the blood-brain and blood-cerebrospinal fluid barriers.

Cited by 391 publications

References 38 publications

Clusterin and LRP2 are critical components of the hypothalamic feeding regulatory pathway

Clusterin and LRP2 are critical components of the hypothalamic feeding regulatory pathway

Clearance mechanisms of Alzheimer's amyloid-β peptide: implications for therapeutic design and diagnostic tests

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

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