Effects of human LDLR overexpression on apoE-related tau pathology and brain dysfunction

Abstract

Abstract ApoE4 is the strongest genetic risk factor for late-onset Alzheimer Disease. It has been reported that apoE isoforms directly affect tauopathy and tau-mediated neurodegeneration in P301S tau transgenic mice expressing different human apoE isoforms, with apoE4 resulting in markedly increased tau-mediated neurodegeneration and the absence of apoE being marked protective against neurodegeneration. In the brain, low-density lipoprotein receptor (LDLR) is one of the main apoE receptors that regulates apoE levels, but LDLR has very few identified ligands compared to other apoE receptors. LDLR overexpression in the brain can dramatically lower apoE and Aβ levels, as well as decrease Aβ accumulation and deposition. Therefore, we propose to evaluate whether AAV-mediated overexpression of human LDLR (hLDLR) is an efficient way to reduce apoE levels, tau pathology, and neurodegeneration. To study the effect of LDLR overexpression on apoE4-related tau pathology and neurodegeneration, P301S Tau/ApoE4 (TE4) male mice received bilateral intracerebroventricular injection with AAV expressing hLDLR or GFP-control, starting before the onset of tau pathology development. Brains were isolated after 9 month, divided into hemispheres, and analyzed by histological and biochemical techniques. Widespread expression of hLDLR throughout the brain was observed and apoE levels were significantly decreased. Furthermore, mouse nest-building impairment was rescued after hLDLR overexpression. Strikingly, there is a significant decrease in brain atrophy, phosphorylated tau deposition in TE4 mice overexpressing hLDLR. In summary, these data suggest that LDLR may be a promising target to lower apoE levels and decrease neurodegeneration.