Activation of the amyloid cascade in apolipoprotein E4 transgenic mice induces lysosomal activation and neurodegeneration resulting in marked cognitive deficits.
ABSTRACT The allele E4 of apolipoprotein E (apoE4), the most prevalent genetic risk factor for Alzheimer's disease, is associated histopathologically with elevated levels of brain amyloid. This led to the suggestion that the pathological effects of apoE4 are mediated by cross-talk interactions with amyloid beta peptide (Abeta), which accentuate the pathological effects of the amyloid cascade. The mechanisms underlying the Abeta-mediated pathological effects of apoE4 are unknown. We have shown recently that inhibition of the Abeta-degrading enzyme neprilysin in brains of wild-type apoE3 and apoE4 mice results in rapid and similar elevations in their total brain Abeta levels. However, the nucleation and aggregation of Abeta in these mice were markedly affected by the apoE genotype and were specifically enhanced in the apoE4 mice. We presently used the neprilysin inhibition paradigm to analyze the neuropathological and cognitive effects that are induced by apoE4 after activation of the amyloid cascade. This revealed that apoE4 stimulates isoform specifically the degeneration of hippocampal CA1 neurons and of entorhinal and septal neurons, which is accompanied by the accumulation of intracellular Abeta and apoE and with lysosomal activation. Furthermore, these neuropathological effects are associated isoform specifically with the occurrence of pronounced cognitive deficits in the ApoE4 mice. These findings provide the first in vivo evidence regarding the cellular mechanisms underlying the pathological cross talk between apoE4 and Abeta, as well as a novel model system of neurodegeneration in vivo that is uniquely suitable for studying the early stages of the amyloid cascade and the effects thereon of apoE4.
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ABSTRACT: Apolipoprotein E4 (apoE4), the most prevalent genetic risk factor for Alzheimer's disease (AD), is less lipidated than its corresponding AD-benign form, apoE3, and it has been suggested that the pathological effects of apoE4 are mediated by lipid-related mechanisms. ATP-binding cassette transporters A1 and G1 (ABCA1 and ABCG1, respectively) are the most important apoE-lipidating proteins. The expression of these proteins, as well as that of apoE, is controlled by the transcription regulation retinoid X receptor (RXR)-liver X receptor (LXR) system. In the present study, we investigated the effects of the RXR agonist bexarotene on mRNA and protein levels of apoE, ABCA1, and ABCG1 in young, naive apoE3- and apoE4-targeted replacement mice and assessed the extent to which this reverses the apoE4-driven pathological phenotype. This investigation reveled that bexarotene increases the mRNA and protein levels of ABCA1 and ABCG1 in hippocampal neurons, but has no effect on the corresponding levels of apoE. These findings were associated with reversal of the lipidation deficiency of apoE4 and of the cognitive impairments of apoE4 mice in several tests. Furthermore, bexarotene reversed the apoE4-driven accumulation of Aβ42 and hyperphosphorylated tau in hippocampal neurons, as well as the apoE4-induced reduction in the levels of the presynaptic marker vesicular glutamatergic transporter 1 (VGluT1). In conclusion, the results show that treatment of apoE4 mice with the RXR agonist bexarotene reverses the apoE4-induced cognitive and neuronal impairments in vivo and suggest that this is due to reversal of the lipidation deficiency of apoE4. This puts forward the possibility that RXR activation and increased levels of ABCA1 and ABCG1 could be useful in the treatment of human apoE4 carriers.Journal of Neuroscience 05/2014; 34(21):7293-301. · 6.75 Impact Factor
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ABSTRACT: Purpose The purpose of this study was to determine if antioxidant supplementation, moderate exercise, and the combination of both treatments could ameliorate cognitive performance in adult mice and whether the apolipoprotein E (APOE) genotype as well as sex could influence the functional outcomes of the treatments. Methods For a period of 16 weeks, separate groups of male and female mice expressing either the human APOE3 or APOE4 isoforms were fed either a control diet (NIH-31) or the control diet supplemented with vitamins E and C (1.12 IU/g diet α-tocopheryl acetate and 1.65 mg/g ascorbic acid). The mice were further separated into a sedentary group or a group that followed a daily exercise regimen. After 8 weeks on the treatments, the mice were administered a battery of functional tests including tests to measure cognitive and affective function. Results There was no effect of genotype or treatment on the learning performance in the Morris water maze. In the discriminated avoidance task, APOE4 mice performed better in learning the discrimination component of the task. Overall, exercise improved performance of APOE4 and APOE3 mice on various aspects of the active avoidance task. Antioxidant supplementation improved performance only in the APOE4 mice. On the test for anxiety, APOE4 mice spent more time in the open arms and supplementation with antioxidant reversed that effect. Conclusion Exercise was the most effective treatment at improving cognitive function in both genotypes and sex, while antioxidants seemed to be effective only in the APOE4. In young adult mice only non-spatial learning and memory were improved. The combination of the two treatments did not yield further improvement in cognition, and there was no antagonistic action of the antioxidant supplementation on the beneficial effects of exercise.Journal of Sport and Health Science 09/2014; · 1.23 Impact Factor
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ABSTRACT: Deposition of amyloid-β (Aβ) in Alzheimer's disease (AD) is strongly correlated with APOE genotype. However, the role of apoE on Aβ aggregation has remained unclear. Here we have used different apoE preparations, such as recombinant or protein isolated from cultured astrocytes, to examine the effect of apoE on the aggregation of both Aβ1-40 and Aβ1-42. The kinetics of aggregation, measured by loss of fluorescence of tetramethylrhodamine-labeled Aβ, is shown to be dramatically slowed by the presence of sub-stoichiometric concentrations of apoE. Using these concentrations, we conclude that apoE binds primarily to and affects the growth of oligomers that lead to the nuclei required for fibril growth. At higher apoE concentrations the protein also binds to Aβ fibrils resulting in fibril stabilization and a slower rate of fibril growth. The aggregation of Aβ1-40 is apoE isoform dependent being most dramatic for apoE4 and less so for apoE3 and apoE2. Our results indicate that the detrimental role of apoE4 in AD could be related to apoE induced stabilization of the soluble but cytotoxic oligomeric and intermediates of Aβ, as well as fibril stabilization.Biochemistry 09/2014; · 3.38 Impact Factor