Human apoE3 but not apoE4 rescues impaired astrocyte activation in apoE null mice

Ophir, Gal; Meilin, Sigal; Efrati, Margalit; Chapman, Joab; Karussis, Dimitri; Roses, Allen D.; Michaelson, Daniel M.

doi:10.1016/s0969-9961(02)00005-0

Cited by 47 publications

(35 citation statements)

References 54 publications

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“…Animal studies have also shown that transgenic mice expressing the human ε4 allele have more pronounced brain inflammatory responses than mice expressing the ε3 allele. 33,34 Finally, several studies in vitro and in vivo have suggested that certain NSAIDs selectively lower Aβ 42 . Because Aβ 42 may play a central role in AD pathogenesis, these findings have suggested the hypothesis that only the selective Aβ 42 -lowering agents (SALAs) should lower the risk of AD in humans.…”

Section: Discussionmentioning

confidence: 99%

NSAID use and dementia risk in the Cardiovascular Health Study*

et al. 2008

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Section: Discussionmentioning

confidence: 99%

NSAID use and dementia risk in the Cardiovascular Health Study*

et al. 2008

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“…Frozen brain coronal sections (10 m) were cut and stained immunohistochemically as described in ref. 34. Sections were viewed and photographed at ϫ40 magnification by using a Supercam camera (Applitec, Holon, Israel).…”

Section: Methodsmentioning

confidence: 99%

“…The apoE genotype of the mice was confirmed by PCR analysis, as described in ref. 34.Mice (5-month-old males) were divided into groups bearing either the human apoE3 or apoE4 transgene. A third and fourth group comprised, respectively, apoE-deficient mice that were pooled siblings of these transgenic mice (35) and C57BL͞65 controls.…”

mentioning

confidence: 99%

A nontransgenic mouse model shows inducible amyloid-β (Aβ) peptide deposition and elucidates the role of apolipoprotein E in the amyloid cascade

Dolev

Michaelson

2004

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

102

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The amyloid-␤ (A␤) peptide, a major pathological hallmark of Alzheimer's disease (AD), undergoes a cascade of interactions resulting in the formation of soluble aggregates and their conversion in the brain to insoluble deposits and mature senile plaques. Furthermore, the apoE4 isoform of apolipoprotein E (apoE), which is the major genetic risk factor of AD, is associated with increased A␤ deposition. It is not known how the different A␤ aggregates in the amyloid cascade are formed, contribute to the pathogenesis of AD, or are affected by apoE4. To investigate the initial aggregation stages underlying the amyloid cascade in vivo and how apoE affects them, we examined the effects of prolonged inhibition and subsequent reactivation of the A␤-degrading protease neprilysin on deposition, disaggregation, and fibrillization of A␤ in apoEtransgenic and control mice. In control mice, intracerebroventricular infusion of thiorphan, which inhibits neprilysin, induced A␤42 and A␤40 deposition and fibrillization. On termination of thiorphan treatment, the number of A␤ deposits decreased, whereas the fibrillar A␤ deposits were unaffected. Similar treatments in apoE-deficient mice and mice transgenic for human apoE4 or apoE3 revealed that apoE4 enhances specifically the nucleation and aggregation of immunopositive A␤ deposits and that reversible disaggregation of these deposits and their irreversible conversion to fibrillar deposits are stimulated similarly by the different apoE isoforms. Deposition of A␤ and its enhancement by apoE4 were accompanied by increased astrogliosis both far from and near the A␤ deposits, suggesting that astrogliosis might be triggered by both insoluble and soluble A␤ aggregates.C onverging genetic and histopathological observations led to the formulation of the amyloid hypothesis, which proposes that accumulation of amyloid-␤ (A␤) peptide, a major constituent of the brain plaques characteristic of Alzheimer's disease (AD), is the primary event in AD pathogenesis (1, 2). Recent findings suggest that brains of individuals with AD also contain soluble and neurotoxic A␤ oligomers, which seem to be an intermediate state in the A␤-aggregation cascade, whose downstream product is the senile plaque (3-10). There is poor correlation between the severity of dementia and the density of amyloid plaques in AD (11-13); furthermore, in mice transgenic for the human A␤ precursor protein (APP), synaptic degeneration and cognitive decline are observed even before amyloid is deposited (14-16). This finding suggests that the pathological effects of A␤ in AD are mediated by A␤ aggregates that precede the formation of the senile plaque. The relative contributions of the different soluble and insoluble A␤ aggregates to the pathology of AD and the mechanisms underlying their formation in vivo are not yet known.Apolipoprotein E (apoE), the major brain lipid-binding protein, is expressed in humans as three isoforms (apoE2, apoE3, and apoE4), which differ in one or two amino acids (17). The apoE4 genotype is the major genetic ...

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“…Data on the impact of apoE genotype on the macrophage inflammatory response are very limited. In a recent studies by Ophir et al (2003Ophir et al ( , 2005 and Lynch et al (2003) higher production of proinflammatory cytokines in the brain and serum was observed in E4 v. E3 transgenic mice following injection with lipopolysaccharide (inflammatory stimulus). The study of Lynch et al (2003) highlights that the impact of genotype is largely attributable to a differential impact of E3 v. E4 on NF-kB signalling, which may be attributable to apoE genotype-mediated differences in oxidative status.…”

Section: Apoe No Production and Inflammatory Statusmentioning

confidence: 95%

ApoE genotype, cardiovascular risk and responsiveness to dietary fat manipulation

et al. 2007

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Cardiovascular risk is determined by the complex interactions between genetic and environmental factors. The apoE genotype represents the most-widely-studied single nucleotide polymorphism in relation to CVD risk, with > 3600 publications cited in PubMed. Although originally described as a mediator of lipoprotein metabolism, the lipoprotein-independent functions of apoE are being increasingly recognised, with limited data available on the potential impact of genotype on these metabolic processes. Furthermore, although meta-analyses suggest that apoE4 carriers may have a 40-50% increased CVD risk, the associations reported in individual studies are highly heterogeneous and it is recognised that environmental factors such as smoking status and dietary fat composition influence genotype-phenotype associations. However, information is often derived from observational studies or small intervention trials in which retrospective genotyping of the cohort results in small group sizes in the rarer E2 and E4 subgroups. Either larger well-standardised intervention trials or smaller trials with prospective recruitment according to apoE genotype are needed to fully establish the impact of diet on genotype-CVD associations and to establish the potential of dietary strategies such as reduced total fat, saturated fat, or increased antioxidant intakes to counteract the increased CVD burden in apoE4 carriers. ApoE genotype: CVD: Dietary fat: Oxidative status: InflammationThe impact of single nucleotide polymorphisms on risk of chronic diseases such as CVD, and the ability of dietary factors to manipulate genotype-phenotype associations, is being increasingly recognised. Undoubtedly, the mostwidely-studied gene variant in relation to CVD is the apoE e (e2, e3, e4) genotype. Since its discovery in 1973 the central role of the apoE protein in lipoprotein metabolism has been comprehensively investigated and reported. The 40-50 % higher risk of CVD in apoE4 carriers (Song et al. 2004) has been traditionally attributed to moderately higher circulating cholesterol and TAG levels. However, it is becoming increasingly recognised that an effect on lipoprotein metabolism alone cannot explain the disease differential and that the impact of an apoE4 genotype is largely lipoprotein independent. Roles of macrophagederived apoE protein on vascular health and atherogenesis are being identified, with apoE thought to impact on oxidative status and in an autocrine and paracrine manner affect macrophage, vascular smooth muscle cell, endothelial cell and platelet function. An impact of genotype on these localised functions of apoE could in part explain the impact of genotype on CVD pathology, as will be discussed.Additionally, apoE genotype has been shown to affect the responsiveness to the total fat content and fatty acid composition of the diet. Manipulation of dietary fat content may serve as a means of reducing the increased CVD burden associated with an apoE4 genotype.

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Human apoE3 but not apoE4 rescues impaired astrocyte activation in apoE null mice

Cited by 47 publications

References 54 publications

NSAID use and dementia risk in the Cardiovascular Health Study*

NSAID use and dementia risk in the Cardiovascular Health Study*

A nontransgenic mouse model shows inducible amyloid-β (Aβ) peptide deposition and elucidates the role of apolipoprotein E in the amyloid cascade

ApoE genotype, cardiovascular risk and responsiveness to dietary fat manipulation

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