Impact of Apolipoprotein E (ApoE) Polymorphism on Brain ApoE Levels

Discovery Neuroscience, Wyeth Research, CN8000, Princeton, New Jersey 08543, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 12/2008; 28(45):11445-53. DOI: 10.1523/JNEUROSCI.1972-08.2008
Source: PubMed

ABSTRACT Inheritance of the apoE4 allele (epsilon4) increases the risk of developing Alzheimer's disease; however, the mechanisms underlying this association remain elusive. Recent data suggest that inheritance of epsilon4 may lead to reduced apoE protein levels in the CNS. We therefore examined apoE protein levels in the brains, CSF and plasma of epsilon2/2, epsilon3/3, and epsilon4/4 targeted replacement mice. These apoE mice showed a genotype-dependent decrease in apoE levels; epsilon2/2 >epsilon3/3 >epsilon4/4. Next, we sought to examine the relative contributions of apoE4 and apoE3 in the epsilon3/4 mouse brains. ApoE4 represented 30-40% of the total apoE. Moreover, the absolute amount of apoE3 per allele was similar between epsilon3/3 and epsilon3/4 mice, implying that the reduced levels of total apoE in epsilon3/4 mice can be explained by the reduction in apoE4 levels. In culture medium from epsilon3/4 human astrocytoma or epsilon3/3, epsilon4/4 and epsilon3/4 primary astrocytes, apoE4 levels were consistently lower than apoE3. Secreted cholesterol levels were also lower from epsilon4/4 astrocytes. Pulse-chase experiments showed an enhanced degradation and reduced half-life of newly synthesized apoE4 compared with apoE3. Together, these data suggest that astrocytes preferentially degrade apoE4, leading to reduced apoE4 secretion and ultimately to reduced brain apoE levels. Moreover, the genotype-dependent decrease in CNS apoE levels, mirror the relative risk of developing AD, and suggest that low levels of total apoE exhibited by epsilon4 carriers may directly contribute to the disease progression, perhaps by reducing the capacity of apoE to promote synaptic repair and/or Abeta clearance.

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    • "Low APOE concentrations or impaired reverse cholesterol transport could thereby hinder efficient lipid evacuation from the RPE to the choroid and lead to drusen development . (Mahley & Rall, 2000; Mooijaart et al, 2006; Riddell et al, 2008; Malek et al, 2005). This hypothesis is, however, in contradiction with the APOE accumulation observed in AMD donor eyes (Klaver et al, 1998; Anderson et al, 2001) and the protective effect of the APOE4 allele in AMD (McKay et al, 2011). "
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    ABSTRACT: Physiologically, the retinal pigment epithelium (RPE) expresses immunosuppressive signals such as FAS ligand (FASL), which prevents the accumulation of leukocytes in the subretinal space. Age-related macular degeneration (AMD) is associated with a breakdown of the subretinal immunosuppressive environment and chronic accumulation of mononuclear phagocytes (MPs). We show that subretinal MPs in AMD patients accumulate on the RPE and express high levels of APOE. MPs of Cx3cr1−/− mice that develop MP accumulation on the RPE, photoreceptor degeneration, and increased choroidal neovascularization similarly express high levels of APOE. ApoE deletion in Cx3cr1−/− mice prevents pathogenic age- and stress-induced subretinal MP accumulation. We demonstrate that increased APOE levels induce IL-6 in MPs via the activation of the TLR2-CD14-dependent innate immunity receptor cluster. IL-6 in turn represses RPE FasL expression and prolongs subretinal MP survival. This mechanism may account, in part, for the MP accumulation observed in Cx3cr1−/− mice. Our results underline the inflammatory role of APOE in sterile inflammation in the immunosuppressive subretinal space. They provide rationale for the implication of IL-6 in AMD and open avenues toward therapies inhibiting pathogenic chronic inflammation in late AMD.
    EMBO Molecular Medicine 01/2015; 7(2). DOI:10.15252/emmm.201404524 · 8.67 Impact Factor
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    • "As a major lipid transporter and redistribution regulator in the brain (Mahley et al, 2006), impaired apoE function exhibited by APOE-e4 carriers may give rise to abnormal cholesterol homeostasis (Jiang et al, 2008; Riddell et al, 2008). "
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    ABSTRACT: Since Apolipoprotein E (APOE) ɛ4 allele is a major genetic risk factor for sporadic Alzheimer's disease (AD), which has been suggested as a disconnection syndrome manifested by the disruption of white matter (WM) integrity and functional connectivity(FC), elucidating the subtle brain structural and functional network changes in cognitively normal ɛ4 carriers is essential for identifying sensitive neuroimaging based biomarkers and understanding the preclinical AD related abnormality development. We first constructed functional network based on the resting-state functional magnetic resonance imaging and structural network based on diffusion tensor image. Using global, local and nodal efficiencies of these two networks, we then examined 1) the differences of functional and WM structural network between cognitively normal ɛ4 carriers and non-carriers simultaneously, 2) the sensitivity of these indices as biomarkers, and 3) their relationship to behavior measurements as well as to cholesterol level. For ɛ4 carriers, we found reduced global efficiency significantly in WM and marginally in FC, regional FC dysfunctions mainly in medial temporal areas, and more widespread for WM network. Importantly, the right parahippocampal gyrus (PHG.R) was the only region with simultaneous functional and structural damage, and the nodal efficiency of PHG.R in WM network mediates the APOE ɛ4 effect on memory function. Finally, the cholesterol level correlated with WM network differently than with functional network in ɛ4 carriers. Our results demonstrated ɛ4-specific abnormal structural and functional patterns, which may potentially serve as biomarkers for early detection before the onset of the disease.Neuropsychopharmacology accepted article preview online, 18 November 2014. doi:10.1038/npp.2014.302.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 11/2014; 40(5). DOI:10.1038/npp.2014.302 · 7.05 Impact Factor
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    • "Indeed, animal and in vitro experiments have suggested that enhanced degradation or defective lipidation of the ApoE4 protein compared with ApoE3 stand as possible explanations for a reduction in total ApoE in tissue [81] [88]. Brain ApoE concentrations are also decreased in AD brain [45] [74] [89] and plasma [90], further arguing for a loss of ApoE activity in AD. "
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    ABSTRACT: A brief overview of the evidence for omega-3 fatty acids and, in particular, of docosahexaenoic acid (DHA), involvement in cognition and in dementia is given. Two studies are presented in this regard in which the key intervention is a DHA supplement. The fist, the MIDAS Study demonstrated that DHA can be of benefit for episodic memory in healthy adults with a mild memory complaint. The second, the ADCS AD trial found no benefit of DHA in the primary outcomes but found an intriguing benefit for cognitive score in ApoE4 negative allele patients. This leads to a consideration of the mechanisms of action and role of ApoE and its modulation by DHA. Given the fundamental role of ApoE in cellular lipid transport and metabolism in the brain and periphery, it is no surprise that ApoE affects n-3 PUFA brain function as well. It remains to be seen to what extent ApoE4 deleterious effect in AD is associated with n-3 PUFA-related cellular mechanisms in the brain and, more specifically, whether ApoE4 directly impairs the transport of DHA into the brain, as has been suggested.
    Prostaglandins Leukotrienes and Essential Fatty Acids 10/2014; 92. DOI:10.1016/j.plefa.2014.10.003 · 2.35 Impact Factor
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