Differential Effects of ApoE Isoforms on Dendritic Spines<i>In Vivo</i>: Linking an Alzheimer's Disease Risk Factor with Synaptic Alterations

Basak, Jacob M.; Kim, Jung-Su

doi:10.1523/jneurosci.0505-10.2010

Cited by 4 publications

(4 citation statements)

References 9 publications

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“…Using another transgenic mouse model where the apoE isoform is expressed in astrocytes, Hartman et al also demonstrated that apoE4 mice were more severely impaired in working memory in a radial arm maze test ( Hartman et al, 2001 ). Other previous studies also reported an association between the apoE4 and spine deficits in vivo ( Basak and Kim, 2010 ; Dumanis et al, 2009 ; Ji et al, 2003 ; Wang et al, 2005 ).…”

Section: Role Of Apoe In Synaptic Plasticity and Cognitionsupporting

confidence: 59%

Apolipoprotein E in Synaptic Plasticity and Alzheimer’s Disease: Potential Cellular and Molecular Mechanisms

Kim¹,

Yoon²,

Basak³

et al. 2014

Molecules and Cells

114

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Alzheimer’s disease (AD) is clinically characterized with progressive memory loss and cognitive decline. Synaptic dysfunction is an early pathological feature that occurs prior to neurodegeneration and memory dysfunction. Mounting evidence suggests that aggregation of amyloid-β (Aβ) and hyperphosphorylated tau leads to synaptic deficits and neurodegeneration, thereby to memory loss. Among the established genetic risk factors for AD, the ɛ4 allele of apolipoprotein E (APOE) is the strongest genetic risk factor. We and others previously demonstrated that apoE regulates Aβ aggregation and clearance in an isoform-dependent manner. While the effect of apoE on Aβ may explain how apoE isoforms differentially affect AD pathogenesis, there are also other underexplored pathogenic mechanisms. They include differential effects of apoE on cerebral energy metabolism, neuroinflammation, neurovascular function, neurogenesis, and synaptic plasticity. ApoE is a major carrier of cholesterols that are required for neuronal activity and injury repair in the brain. Although there are a few conflicting findings and the underlying mechanism is still unclear, several lines of studies demonstrated that apoE4 leads to synaptic deficits and impairment in long-term potentiation, memory and cognition. In this review, we summarize current understanding of apoE function in the brain, with a particular emphasis on its role in synaptic plasticity and the underlying cellular and molecular mechanisms, involving low-density lipoprotein receptor-related protein 1 (LRP1), syndecan, and LRP8/ApoER2.

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Section: Role Of Apoe In Synaptic Plasticity and Cognitionsupporting

confidence: 59%

Apolipoprotein E in Synaptic Plasticity and Alzheimer’s Disease: Potential Cellular and Molecular Mechanisms

Kim¹,

Yoon²,

Basak³

et al. 2014

Molecules and Cells

114

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“…APOE also affects long-term potentiation (i.e., the current in vitro memory model) in an isoform-specific manner (via induction of long-term potentiation: APOE4>APOE3>APOE2) (Korwek et al 2009). APOE isoforms may differentially affect synaptic plasticity and dendritic spine integrity via the modulation of spine elimination (Basak & Kim 2010); as a result of isoformdependent levels of APOE (Basak & Kim 2010, Dumanis et al 2009; and by acting as signaling molecules through interactions with APOE receptors (Chen et al 2010), NMDA receptors (Korwek et al 2009), and a novel intracellular PKCε pathway (Sen et al 2012). Further studies are warranted to determine the exact molecular and cellular mechanisms of these phenomena.…”

Section: The Effect Of Apoe On Synaptic Plasticity Dendritic Spine In...mentioning

confidence: 99%

Apolipoprotein E in Alzheimer's Disease: An Update

Tan

Hardy

2014

Annu. Rev. Neurosci.

366

286

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The vast majority of Alzheimer's disease (AD) cases are late onset (LOAD), which is genetically complex with heritability estimates up to 80%. Apolipoprotein E (APOE) has been irrefutably recognized as the major genetic risk factor, with semidominant inheritance, for LOAD. Although the mechanisms that underlie the pathogenic nature of APOE in AD are still not completely understood, emerging data suggest that APOE contributes to AD pathogenesis through both amyloid-β (Aβ)-dependent and Aβ-independent pathways. Given the central role for APOE in the modulation of AD pathogenesis, many therapeutic strategies have emerged, including converting APOE conformation, regulating APOE expression, mimicking APOE peptides, blocking the APOE/Aβ interaction, modulating APOE lipidation state, and gene therapy. Accumulating evidence also suggests the utility of APOE genotyping in AD diagnosis, risk assessment, prevention, and treatment response.

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“…This may suggest effect modification at the genetic level. Variation at the apolipoprotein E (APOE) gene locus is the most consistent nondeterministic genetic risk factor for late-onset Alzheimer’s dementia 23–26. Its contribution to AD risk is graded across its three known common isoforms (E2, E3, and E4) in humans encoded by ɛ2, ɛ3, and ɛ4 alleles.…”

Section: Introductionmentioning

confidence: 99%

“…Variation at the apolipoprotein E (APOE) gene locus is the most consistent nondeterministic genetic risk factor for late-onset Alzheimer’s dementia. 23 – 26 Its contribution to AD risk is graded across its three known common isoforms (E2, E3, and E4) in humans encoded by ɛ2, ɛ3, and ɛ4 alleles. Whereas, ɛ2 allele is associated with lower risk, ɛ4 associates with increased AD risk, an effect that is differentially influenced by age.…”

Section: Introductionmentioning

confidence: 99%

Association of leisure-time physical activity with cognition by apolipoprotein-E genotype in persons aged 60 years and over: the National Health and Nutrition Examination Survey (NHANES-III)

Obisesan¹,

Umar²,

Paluvoi³

et al. 2012

CIA

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ObjectiveTo test the hypothesis that aerobic-related leisure-time physical activity (PA) is associated with better cognitive function and that the effect varies among apolipoprotein E (APOE) genotype groups.DesignCross-sectional study of persons examined in the Third National Health and Nutrition Examination Survey (NHANES-III; 1988–1994).SettingUS noninstitutionalized population.Participants and methodsFrom a sample of 7159, aged ≥60 years, we analyzed data for 1799 older American men and women who had information on PA, a short mental status examination (SMSE), and were genotyped at the apolipoprotein E gene locus.ResultsIn the initial bivariate analysis, non-ɛ4 carriers and ɛ4-heterozygotes performed better than ɛ4-homozygotes in the 60–69 age group. After controlling for multiple confounders including mobility limitation, PA correlated with a higher SMSE score in non-ɛ4 carriers (P = 0.014), but not in ɛ4 carriers (P = 0.887). At ≥70 years, PA also correlated with higher adjusted SMSE scores in non-ɛ4 carriers (P = 0.02); but this association became nonsignificant after controlling for mobility limitation (P = 0.12).ConclusionIn a nationally representative sample, PA was associated with enhanced cognition, an effect that was differentially influenced by apolipoprotein E genotype. Experimental studies are needed to determine whether or not PA can attenuate cognitive decline.

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Differential Effects of ApoE Isoforms on Dendritic SpinesIn Vivo: Linking an Alzheimer's Disease Risk Factor with Synaptic Alterations

Cited by 4 publications

References 9 publications

Apolipoprotein E in Synaptic Plasticity and Alzheimer’s Disease: Potential Cellular and Molecular Mechanisms

Apolipoprotein E in Synaptic Plasticity and Alzheimer’s Disease: Potential Cellular and Molecular Mechanisms

Apolipoprotein E in Alzheimer's Disease: An Update

Association of leisure-time physical activity with cognition by apolipoprotein-E genotype in persons aged 60 years and over: the National Health and Nutrition Examination Survey (NHANES-III)

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