Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms

APOE is the strongest genetic risk factor for late-onset Alzheimer’s disease. ApoE exacerbates tau-associated neurodegeneration by driving microglial activation. However, how apoE regulates microglial activation and whether targeting apoE is therapeutically beneficial in tauopathy is unclear. Here, we show that overexpressing an apoE metabolic receptor, LDLR (low-density lipoprotein receptor), in P301S tauopathy mice markedly reduces brain apoE and ameliorates tau pathology and neurodegeneration. LDLR overexpression (OX) in microglia cell-autonomously downregulates microglial Apoe expression and is associated with suppressed microglial activation as in apoE-deficient microglia. ApoE deficiency and LDLR OX strongly drive microglial immunometabolism toward enhanced catabolism over anabolism, whereas LDLR-overexpressing microglia also uniquely upregulate specific ion channels and neurotransmitter receptors upon activation. ApoE-deficient and LDLR-overexpressing mice harbor enlarged pools of oligodendrocyte progenitor cells (OPCs) and show greater preservation of myelin integrity under neurodegenerative conditions. They also show less reactive astrocyte activation in the setting of tauopathy. •LDLR OX lowers apoE and reduces tau pathology and neurodegeneration in P301S mice•LDLR-overexpressing microglia downregulate Apoe and show suppressed activation•ApoE KO and LDLR OX drive microglial catabolism over anabolism•ApoE KO and LDLR OX increase the OPC pool and preserve myelin integrity Shi et al. show that apoE regulates tau-associated neurodegeneration via multiple mechanisms, including regulating microglial activation by controlling microglial immunometabolism, regulating OPCs and myelin integrity, and regulating reactive astrocyte activation. LDLR overexpression attenuates tauopathy in part through shared mechanisms of apoE, making LDLR a new therapeutic target for tauopathy treatment.