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Lack of hepatic apoE does not influence early Aβ deposition: observations from a new APOE knock-in model.
Mol Neurodegener. 2019 10 17; 14(1):37.MN

Abstract

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.

Authors+Show Affiliations

Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA. Medical Scientist Training Program (MSTP), Washington University School of Medicine, St. Louis, MO, USA.Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA.Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA.Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA. Medical Scientist Training Program (MSTP), Washington University School of Medicine, St. Louis, MO, USA.Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA.Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA.Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA.Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA.Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA.McCance Center for Brain Health and Genetics and Aging Research Unit, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA.Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA.Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA. holtzman@neuro.wustl.edu.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

31623648

Citation

Huynh, Tien-Phat V., et al. "Lack of Hepatic apoE Does Not Influence Early Aβ Deposition: Observations From a New APOE Knock-in Model." Molecular Neurodegeneration, vol. 14, no. 1, 2019, p. 37.
Huynh TV, Wang C, Tran AC, et al. Lack of hepatic apoE does not influence early Aβ deposition: observations from a new APOE knock-in model. Mol Neurodegener. 2019;14(1):37.
Huynh, T. V., Wang, C., Tran, A. C., Tabor, G. T., Mahan, T. E., Francis, C. M., Finn, M. B., Spellman, R., Manis, M., Tanzi, R. E., Ulrich, J. D., & Holtzman, D. M. (2019). Lack of hepatic apoE does not influence early Aβ deposition: observations from a new APOE knock-in model. Molecular Neurodegeneration, 14(1), 37. https://doi.org/10.1186/s13024-019-0337-1
Huynh TV, et al. Lack of Hepatic apoE Does Not Influence Early Aβ Deposition: Observations From a New APOE Knock-in Model. Mol Neurodegener. 2019 10 17;14(1):37. PubMed PMID: 31623648.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Lack of hepatic apoE does not influence early Aβ deposition: observations from a new APOE knock-in model. AU - Huynh,Tien-Phat V, AU - Wang,Chao, AU - Tran,Ainsley C, AU - Tabor,G Travis, AU - Mahan,Thomas E, AU - Francis,Caroline M, AU - Finn,Mary Beth, AU - Spellman,Rebecca, AU - Manis,Melissa, AU - Tanzi,Rudolph E, AU - Ulrich,Jason D, AU - Holtzman,David M, Y1 - 2019/10/17/ PY - 2019/06/01/received PY - 2019/08/30/accepted PY - 2019/10/19/entrez PY - 2019/10/19/pubmed PY - 2020/6/24/medline KW - Albumin KW - Amyloid KW - Apolipoprotein E KW - Aβ KW - Cre-loxP KW - Mouse model KW - apoE KW - apoE particle SP - 37 EP - 37 JF - Molecular neurodegeneration JO - Mol Neurodegener VL - 14 IS - 1 N2 - 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. SN - 1750-1326 UR - https://www.unboundmedicine.com/medline/citation/31623648/Lack_of_hepatic_apoE_does_not_influence_early_Aβ_deposition:_observations_from_a_new_APOE_knock_in_model_ DB - PRIME DP - Unbound Medicine ER -