Yang Shi, Prabhakar Sairam Andhey, Christina Ising, Kairuo Wang, Lisa L Snipes, Kevin Boyer, Stephanie Lawson, Kaoru Yamada, Wei Qin, Melissa Manis, Javier Remolina Serrano, Bruno A Benitez, Robert E Schmidt, Maxim Artyomov, Jason D Ulrich, David M Holtzman
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...
August 4, 2021: Neuron