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Apolipoprotein E (APOE) is a strong genetic risk factor for late-onset Alzheimer's disease (LOAD). APOE4 increases and APOE2 decreases risk relative to APOE3. In the P301S mouse model of tauopathy, ApoE4 increases tau pathology and neurodegeneration when compared with ApoE3 or the absence of ApoE. However, the role of ApoE isoforms and lipid metabolism in contributing to tau-mediated degeneration is unknown. We demonstrate that in P301S tau mice, ApoE4 strongly promotes glial lipid accumulation and perturbations in cholesterol metabolism and lysosomal function. Increasing lipid efflux in glia via an LXR agonist or Abca1 overexpression strongly attenuates tau pathology and neurodegeneration in P301S/ApoE4 mice. We also demonstrate reductions in reactive astrocytes and microglia, as well as changes in cholesterol biosynthesis and metabolism in glia of tauopathy mice in response to LXR activation. These data suggest that promoting efflux of glial lipids may serve as a therapeutic approach to ameliorate tau and ApoE4-linked neurodegeneration., Competing Interests: Declaration of interests D.M.H. is on the scientific advisory board of C2N diagnostics and has equity. D.M.H. is on the scientific advisory board of Denali Therapeutics, Genentech, and Cajal Therapeutics and consults for Asteroid Therapeutics. J.H.S., J.L.G., H.P.B., S.S.D., and G.D.P. are full-time employees and shareholders of Denali Therapeutics Inc. K.L. and N.B.-L. are former employees of Denali Therapeutics Inc., (Copyright © 2023 Elsevier Inc. All rights reserved.)

A recent case report described an individual who was a homozygous carrier of the APOE3 Christchurch (APOE3ch) mutation and resistant to autosomal dominant Alzheimer's Disease (AD) caused by a PSEN1-E280A mutation. Whether APOE3ch contributed to the protective effect remains unclear. We generated a humanized APOE3ch knock-in mouse and crossed it to an amyloid-β (Aβ) plaque-depositing model. We injected AD-tau brain extract to investigate tau seeding and spreading in the presence or absence of amyloid. Similar to the case report, APOE3ch expression resulted in peripheral dyslipidemia and a marked reduction in plaque-associated tau pathology. Additionally, we observed decreased amyloid response and enhanced microglial response around plaques. We also demonstrate increased myeloid cell phagocytosis and degradation of tau aggregates linked to weaker APOE3ch binding to heparin sulfate proteoglycans. APOE3ch influences the microglial response to Aβ plaques, which suppresses Aβ-induced tau seeding and spreading. The results reveal new possibilities to target Aβ-induced tauopathy., Competing Interests: Declaration of interests D.M.H. is an inventor on a patent licensed by Washington University to C2N Diagnostics on the therapeutic use of anti-tau antibodies. D.M.H. co-founded and is on the scientific advisory board of C2N Diagnostics. D.M.H. is on the scientific advisory board of Denali, Genentech, and Cajal Neuroscience and consults for Asteroid, and is on the Advisory Board for Cell. M.C. is a member of Vigil Neuro scientific advisory board (SAB), is consultant for Cell Signaling Technology and NGM Bio. The rest of the authors have no conflict of interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Anti-amyloid antibodies are moving from clinical trials into patients to treat early clinical stages of Alzheimer's disease.

Background: The apolipoprotein E (APOE) gene is the strongest genetic risk factor for late-onset Alzheimer disease (AD). ApoE is produced by both astrocytes and microglia in the brain, whereas hepatocytes produce the majority of apoE found in the periphery. Studies using APOE knock-in and transgenic mice have demonstrated a strong isoform-dependent effect of apoE on the accumulation of amyloid-β (Aβ) deposition in the brain in the form of both Aβ-containing amyloid plaques and cerebral amyloid angiopathy. However, the specific contributions of different apoE pools to AD pathogenesis remain unknown., Methods: We have begun to address these questions by generating new lines of APOE knock-in (APOE-KI) mice (ε2/ε2, ε3/ε3, and ε4/ε4) where the exons in the coding region of APOE are flanked by loxP sites, allowing for cell type-specific manipulation of gene expression. We assessed these mice both alone and after crossing them with mice with amyloid deposition in the brain. Using biochemical and histological methods. We also investigated how removal of APOE expression from hepatocytes affected cerebral amyloid deposition., Results: As in other APOE knock-in mice, apoE protein was present predominantly in astrocytes in the brain under basal conditions and was also detected in reactive microglia surrounding amyloid plaques. Primary cultured astrocytes and microglia from the APOE-KI mice secreted apoE in lipoprotein particles of distinct size distribution upon native gel analysis with microglial particles being substantially smaller than the HDL-like particles secreted by astrocytes. Crossing of APP/PS1 transgenic mice to the different APOE-KI mice recapitulated the previously described isoform-specific effect (ε4 > ε3) on amyloid plaque and Aβ accumulation. Deletion of APOE in hepatocytes did not alter brain apoE levels but did lead to a marked decrease in plasma apoE levels and changes in plasma lipid profile. Despite these changes in peripheral apoE and on plasma lipids, cerebral accumulation of amyloid plaques in APP/PS1 mice was not affected., Conclusions: Altogether, these new knock-in strains offer a novel and dynamic tool to study the role of APOE in AD pathogenesis in a spatially and temporally controlled manner.