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| Home > Publications Database > M159. Overexpression of Low-Density LipoproteinReceptor Markedly Reduces Tau Pho sphorylation andAttenuates Tau-Mediated Neurodegeneration via APOE-Mediated Mechanisms |
| Home > Publications Database > M159. Overexpression of Low-Density LipoproteinReceptor Markedly Reduces Tau Pho sphorylation andAttenuates Tau-Mediated Neurodegeneration via APOE-Mediated Mechanisms |
| Abstract/Journal Article | DZNE-2020-01023 |
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2019
Abstract: APOE4 is the strongest genetic risk factor for late-onset Alz-heimer’s disease. While APOE influences brain amyloid-β(Aβ) pathology via affecting Aβ aggregation and clearance,recent findings reveal an Aβ-independent role of APOE inregulating tau-mediated neurodegeneration. APOE ablationin P301S tau transgen ic mice markedly reduces tau-associated brain atrophy and neuroinflammation, and shiftstau pathology towards an early-disease pattern. Hence, tar-geting APOE may be an efficient therapeutic approach toameliorate tau-mediated neurodegeneration. Low densitylipoprotein rece ptor (LDLR) is a major cellular receptor forAPOE. By generating P301S mice carrying a PrP-drivenLDLR transgene overexpressing murine LDLR by over10 fold in the brain, we found that P301S/LDLR miceexhibit significantly reduced brain atrophy an d increasedbrain weight. LDLR overexpression reduced soluble brainAPOE levels by ~90% without altering soluble or insolubletau levels, but markedly reduced phospho-ta u (ptau) levels in salt- soluble and detergent-soluble fractions and shiftedptau pathology towards early-disease patterns, a phenotyperesembling APOE-deficient P301S mice. APOE levelsstrongly correlate with ptau levels in all fractions, and corre-late with less soluble tau and more insoluble tau. InP301S/LDLR mice, we found LDLR is also overexpressedin mic roglia, resulting in an >10-fold intracellular reductionof APOE in microglia. Correspondingly, P301S/LDLRmice show significantly mitigated microglial activation rela-tive to P301S mice. Single nucleus RNA-seq analysis revealssharp Apoe upregulation uniquely in microglia in P301Smouse brain compared to wildtype mice, which is signifi-cantly atte nuated in P301S/LDLR mice, indicating a likelykey r ole of mic roglial APOE in neurodegeneration in thismodel. Overall, our data suggest that increasing LDLRexpression mitigates neurodegeneration in a tauopathymouse model via APOE-mediated mechanisms, and mayconstitute an effective therapeutic approach in AD/tauopa-thy treatment.
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