In vivo measurement of apolipoprotein E from the brain interstitial fluid using microdialysis

Ulrich, Jason D.; Burchett, Jack M.; Restivo, Jessica L.; Schuler, Dorothy R.; Verghese, Philip B.; Mahan, Thomas E.; Landreth, Gary E.; Castellano, Joseph M.; Jiang, Hong; Cirrito, John R.; Holtzman, David M.

doi:10.1186/1750-1326-8-13

Cited by 110 publications

(99 citation statements)

References 27 publications

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“…apoE is found in a class of HDL-like lipoprotein in the cerebrospinal fluid (CSF) and interstitial fluid (ISF) of the brain (12,13). In the periphery, apoE is associated with many different classes of lipoproteins, including VLDLs, intermediate density lipoproteins, chylomicron remnants, and a subclass of HDL (6).…”

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confidence: 99%

Apolipoprotein E and Alzheimer's disease: the influence of apolipoprotein E on amyloid-β and other amyloidogenic proteins

Huynh

Davis

Ulrich

et al. 2017

Journal of Lipid Research

180

145

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In 1907, the German psychiatrist, Alois Alzheimer, published a case report, "On an unusual illness of the cerebral cortex," in which he described what we now know as Alzheimer's disease (AD) (1). More than a century after this landmark discovery, AD is now recognized as the most common cause of late-life dementia. AD pathology is characterized by the cerebral accumulation of amyloid plaques and neurofibrillary tangles, both of which consist predominantly of specific insoluble protein aggregates. The majority of AD cases are sporadic and have a relatively late onset, predominantly after the age of 65. This form of AD is known as late-onset AD (LOAD), in contrast to early-onset AD, which has a strong genetic component, is often autosomal dominant, and accounts for less than 1% of AD cases (2). While most genetic risk factors for LOAD identified in the past two decades have a relatively small impact on AD risk, extensive epidemiological, clinical, and pathological studies have established the APOE gene on chromosome 19 as the most important genetic risk factor for developing LOAD (3-5). This locus encodes a 299 amino acid glycoprotein (apoE) that is expressed in several cell types, with highest expression levels found in the liver and the brain, where it is expressed predominantly by astrocytes (6) and, to a lesser extent, microglia (7,8). The human APOE gene Abstract Alzheimer's disease (AD) is one of the fastestgrowing causes of death and disability in persons 65 years of age or older, affecting more than 5 million Americans alone. Clinical manifestations of AD include progressive decline in memory, executive function, language, and other cognitive domains. Research efforts within the last three decades have identified APOE as the most significant genetic risk factor for late-onset AD, which accounts for >99% of cases. The apoE protein is hypothesized to affect AD pathogenesis through a variety of mechanisms, from its effects on the blood-brain barrier, the innate immune system, and synaptic function to the accumulation of amyloid- (A). Here, we discuss the role of apoE on the biophysical properties and metabolism of the A peptide, the principal component of amyloid plaques and cerebral amyloid angiopathy (CAA). CAA is characterized by the deposition of amyloid proteins (including A) in the leptomeningeal medium and small arteries, which is found in most AD cases but sometimes occurs as an independent entity. Accumulation of these pathologies in the brain is one of the pathological hallmarks of AD. Beyond A, we will extend the discussion to the potential role of apoE on other amyloidogenic proteins found in AD, and also a number of diverse neurodegenerative diseases.

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confidence: 99%

Apolipoprotein E and Alzheimer's disease: the influence of apolipoprotein E on amyloid-β and other amyloidogenic proteins

Huynh

Davis

Ulrich

et al. 2017

Journal of Lipid Research

180

145

View full text Add to dashboard Cite

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“…Although we could not detect differences in the amount of total proteins in each APOE2/3/4 ACM, APOE2, 3, or 4 KI astrocytes could potentially produce different amount of APOE particles (23), as well as different sets of secreted proteins, affecting astrocyte-mediated phagocytosis. To test whether APOE2/3/4 molecules are directly responsible for differential phagocytic activities of ACM, we prepared lipidated recombinant apoE2, 3, and 4 particles and used these particles for our in vitro engulfment assay instead of ACM (24).…”

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confidence: 74%

Novel allele-dependent role for APOE in controlling the rate of synapse pruning by astrocytes

Chung

Verghese

Chakraborty

et al. 2016

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

185

151

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The strongest genetic risk factor influencing susceptibility to lateonset Alzheimer's disease (AD) is apolipoprotein E (APOE) genotype. APOE has three common isoforms in humans, E2, E3, and E4. The presence of two copies of the E4 allele increases risk by ∼12-fold whereas E2 allele is associated with an ∼twofold decreased risk for AD. These data put APOE central to AD pathophysiology, but it is not yet clear how APOE alleles modify AD risk. Recently we found that astrocytes, a major central nervous system cell type that produces APOE, are highly phagocytic and participate in normal synapse pruning and turnover. Here, we report a novel role for APOE in controlling the phagocytic capacity of astrocytes that is highly dependent on APOE isoform. APOE2 enhances the rate of phagocytosis of synapses by astrocytes, whereas APO4 decreases it. We also found that the amount of C1q protein accumulation in hippocampus, which may represent the accumulation of senescent synapses with enhanced vulnerability to complement-mediated degeneration, is highly dependent on APOE alleles: C1q accumulation was significantly reduced in APOE2 knock-in (KI) animals and was significantly increased in APOE4 KI animals compared with APOE3 KI animals. These studies reveal a novel allele-dependent role for APOE in regulating the rate of synapse pruning by astrocytes. They also suggest the hypothesis that AD susceptibility of APOE4 may originate in part from defective phagocytic capacity of astrocytes which accelerates the rate of accumulation of C1q-coated senescent synapses, enhancing synaptic vulnerability to classical-complement-cascade mediated neurodegeneration.A lzheimer's disease (AD), the most common cause of dementia, is characterized clinically by a progressive and irreversible loss of cognitive functions. The neuropathological hallmarks of AD include profound synaptic loss and selective neuronal cell death, as well as the formation of extracellular amyloid beta plaques (Aβ) (1) and intracellular neurofibrillary tangles (2). Most cases of AD are the late-onset form, which develops after age 60. The causes of lateonset AD are not yet completely understood; however, genetic studies have shown that apolipoprotein E (APOE) alleles profoundly affect AD susceptibility, with APOE4 being the major genetic risk factor. APOE, a 299-amino acid lipid transport protein, has three common isoforms in humans-APOE2 (Cys-112 and -158), APOE3 (Cys-112 and Arg-158), and APOE4 (Arg-112 and -158)-that are products of alleles at a single gene locus (3, 4). The APOE3 is the most common and mediates intermediate risk for AD. The APOE4 allele is significantly overrepresented in lateonset AD patients and has a dosage effect on the risk and age of onset of AD (5), whereas APOE2 is protective against AD (6). Moreover, recent whole-genome sequencing of humans that age without developing diseases showed that there is a significant depletion of APOE4 alleles in the healthy aging population (7). How do different APOE isoforms influence the age of onset and course of d...

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“…Bexarotene [154][155][156] RAGE-binding competitors TTP488, FPS-ZM1 [157] Neuroprotective strategies Neurotrophins BDNF gene therapy [166] Soluble Nogo-receptors Soluble Nogo-66 receptor [167] Acetylcholine esterase inhibitors Donepezil, rivastigmine, galantamine [162,163] Voltage-dependent NMDA receptor agonists Memantine [158][159][160] Anti-histamine drugs Latrepirdine [161] Group IV PLA2 targets Quinacrine, CHEC-9 [164] One protein, multiple pathologies: multifaceted involvement of amyloid b in… also reduce Ab deposition. Gonadotropin-releasing hormone (GRH) agonist leuprolide, suppresses LH by downregulating pituitary GRH receptors and is suggested to be an effective treatment for AD [131].…”

Section: Rxr Agonistsmentioning

confidence: 99%

One protein, multiple pathologies: multifaceted involvement of amyloid β in neurodegenerative disorders of the brain and retina

Gupta

Chitranshi

et al. 2016

Cell. Mol. Life Sci.

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Accumulation of amyloid β (Aβ) and its aggregates in the ageing central nervous system is regarded synonymous to Alzheimer's disease (AD) pathology. Despite unquestionable advances in mechanistic and diagnostic aspects of the disease understanding, the primary cause of Aβ accumulation as well as its in vivo roles remains elusive; nonetheless, the majority of the efforts to address pathological mechanisms for therapeutic development are focused towards moderating Aβ accumulation in the brain. More recently, Aβ deposition has been identified in the eye and is linked with distinct age-related diseases including age-related macular degeneration, glaucoma as well as AD. Awareness of the Aβ accumulation in these markedly different degenerative disorders has led to an increasing body of work exploring overlapping mechanisms, a prospective biomarker role for Aβ and the potential to use retina as a model for brain related neurodegenerative disorders. Here, we present an integrated view of current understanding of the retinal Aβ deposition discussing the accumulation mechanisms, anticipated impacts and outlining ameliorative approaches that can be extrapolated to the retina for potential therapeutic benefits. Further longitudinal investigations in humans and animal models will determine retinal Aβ association as a potential pathognomonic, diagnostic or prognostic biomarker.

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In vivo measurement of apolipoprotein E from the brain interstitial fluid using microdialysis

Cited by 110 publications

References 27 publications

Apolipoprotein E and Alzheimer's disease: the influence of apolipoprotein E on amyloid-β and other amyloidogenic proteins

Apolipoprotein E and Alzheimer's disease: the influence of apolipoprotein E on amyloid-β and other amyloidogenic proteins

Novel allele-dependent role for APOE in controlling the rate of synapse pruning by astrocytes

One protein, multiple pathologies: multifaceted involvement of amyloid β in neurodegenerative disorders of the brain and retina

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