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Cholesterol and Matrisome Pathways Dysregulated in Human APOE ∊4 Glia

56 Pages Posted: 11 Aug 2019 Sneak Peek Status: Review Complete

See all articles by Julia TCW

Julia TCW

Mount Sinai Health System, Icahn School of Medicine, Nash Department of Neuroscience; Mount Sinai Health System, Icahn School of Medicine, Ronald M. Loeb Center for Alzheimer's Disease

Shuang A. Liang

University of California, Irvine - Institute for Memory Impairments and Neurological Disorders

Lu Qian

Mount Sinai Health System, Icahn School of Medicine, Nash Department of Neuroscience; Mount Sinai Health System, Icahn School of Medicine, Ronald M. Loeb Center for Alzheimer's Disease

Nina H. Pipalia

Weill Cornell Medical College - Department of Biochemistry

Michael J. Chao

Mount Sinai Health System, Icahn School of Medicine, Nash Department of Neuroscience; Mount Sinai Health System, Icahn School of Medicine, Ronald M. Loeb Center for Alzheimer's Disease

Sarah E. Bertelsen

Mount Sinai Health System, Icahn School of Medicine, Nash Department of Neuroscience; Mount Sinai Health System, Icahn School of Medicine, Ronald M. Loeb Center for Alzheimer's Disease

Manav Kapoor

Mount Sinai Health System, Icahn School of Medicine, Nash Department of Neuroscience; Mount Sinai Health System, Icahn School of Medicine, Ronald M. Loeb Center for Alzheimer's Disease

Edoardo Marcora

Mount Sinai Health System, Icahn School of Medicine, Nash Department of Neuroscience; Mount Sinai Health System, Icahn School of Medicine, Ronald M. Loeb Center for Alzheimer's Disease

Elizabeth Sikora

Mount Sinai Health System, Icahn School of Medicine, Nash Department of Neuroscience; Mount Sinai Health System, Icahn School of Medicine, Ronald M. Loeb Center for Alzheimer's Disease

David Holtzman

Washington University in St. Louis, School of Medicine, Knight Alzheimer’s Disease Research Center, Hope Center for Neurological Disorders, Department of Neurology

Frederick R. Maxfield

Weill Cornell Medical College - Department of Biochemistry

Bin Zhang

Mount Sinai Health System, Icahn School of Medicine, Department of Genetics and Genomic Sciences

Minghui Wang

Mount Sinai Health System, Icahn School of Medicine, Department of Genetics and Genomic Sciences

Wayne W. Poon

University of California, Irvine - Institute for Memory Impairments and Neurological Disorders

Alison M. Goate

Mount Sinai Health System, Icahn School of Medicine, Nash Department of Neuroscience; Mount Sinai Health System, Icahn School of Medicine, Ronald M. Loeb Center for Alzheimer's Disease; Mount Sinai Health System, Icahn School of Medicine, Department of Genetics and Genomic Sciences

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Abstract

Apolipoprotein E (APOE) ε4 is the strongest genetic risk factor for Alzheimer's disease (AD). Although its association with AD is well-established, the impact of APOE ε4 on human brain cell function remains unclear. Here we investigated the effects of APOE ε4 on brain cell types derived from human induced pluripotent stem cells and human APOE targeted replacement mice. Global transcriptomic profiles showed that APOE ε4 is associated with dysregulation of cholesterol homeostasis in human but not mouse glia. Elevated matrisome signaling in APOE ε4 mixed neuron/astrocyte cultures parallels altered pathways uncovered in cell-type deconvoluted APOE ε4 glia and AD post-mortem brains. In vitro study showed that isogenic APOE ε4 is associated with increased lysosomal cholesterol levels and decreased cholesterol efflux, demonstrating decoupled lipid metabolism. APOE ε4 glia also secrete higher levels of proinflammatory chemokines/cytokines, indicative of glial activation. Thus, APOE ε4 induces human glia-specific dysregulation that may initiate AD risk.

Keywords: APOE, Alzheimer's disease, astrocytes, microglia, cholesterol, matrisome, iPSC, inflammation

Suggested Citation

TCW, Julia and Liang, Shuang A. and Qian, Lu and Pipalia, Nina H. and Chao, Michael J. and Bertelsen, Sarah E. and Kapoor, Manav and Marcora, Edoardo and Sikora, Elizabeth and Holtzman, David and Maxfield, Frederick R. and Zhang, Bin and Wang, Minghui and Poon, Wayne W. and Goate, Alison M., Cholesterol and Matrisome Pathways Dysregulated in Human APOE ∊4 Glia (August 10, 2019). CELL-D-19-02156. Available at SSRN: https://ssrn.com/abstract=3435267 or http://dx.doi.org/10.2139/ssrn.3435267
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Julia TCW (Contact Author)

Mount Sinai Health System, Icahn School of Medicine, Nash Department of Neuroscience ( email )

New York, NY
United States

Mount Sinai Health System, Icahn School of Medicine, Ronald M. Loeb Center for Alzheimer's Disease ( email )

New York, NY 10029
United States

Shuang A. Liang

University of California, Irvine - Institute for Memory Impairments and Neurological Disorders

Irvine, CA
United States

Lu Qian

Mount Sinai Health System, Icahn School of Medicine, Nash Department of Neuroscience ( email )

New York, NY
United States

Mount Sinai Health System, Icahn School of Medicine, Ronald M. Loeb Center for Alzheimer's Disease ( email )

New York, NY 10029
United States

Nina H. Pipalia

Weill Cornell Medical College - Department of Biochemistry ( email )

New York, NY
United States

Michael J. Chao

Mount Sinai Health System, Icahn School of Medicine, Nash Department of Neuroscience ( email )

New York, NY
United States

Mount Sinai Health System, Icahn School of Medicine, Ronald M. Loeb Center for Alzheimer's Disease ( email )

New York, NY 10029
United States

Sarah E. Bertelsen

Mount Sinai Health System, Icahn School of Medicine, Nash Department of Neuroscience ( email )

New York, NY
United States

Mount Sinai Health System, Icahn School of Medicine, Ronald M. Loeb Center for Alzheimer's Disease ( email )

New York, NY 10029
United States

Manav Kapoor

Mount Sinai Health System, Icahn School of Medicine, Nash Department of Neuroscience ( email )

New York, NY
United States

Mount Sinai Health System, Icahn School of Medicine, Ronald M. Loeb Center for Alzheimer's Disease ( email )

New York, NY 10029
United States

Edoardo Marcora

Mount Sinai Health System, Icahn School of Medicine, Nash Department of Neuroscience ( email )

New York, NY
United States

Mount Sinai Health System, Icahn School of Medicine, Ronald M. Loeb Center for Alzheimer's Disease ( email )

New York, NY 10029
United States

Elizabeth Sikora

Mount Sinai Health System, Icahn School of Medicine, Nash Department of Neuroscience ( email )

New York, NY
United States

Mount Sinai Health System, Icahn School of Medicine, Ronald M. Loeb Center for Alzheimer's Disease ( email )

New York, NY 10029
United States

David Holtzman

Washington University in St. Louis, School of Medicine, Knight Alzheimer’s Disease Research Center, Hope Center for Neurological Disorders, Department of Neurology

St. Louis, MO
United States

Frederick R. Maxfield

Weill Cornell Medical College - Department of Biochemistry ( email )

New York, NY
United States

Bin Zhang

Mount Sinai Health System, Icahn School of Medicine, Department of Genetics and Genomic Sciences

1425 Madison Avenue
New York, NY 10029
United States

Minghui Wang

Mount Sinai Health System, Icahn School of Medicine, Department of Genetics and Genomic Sciences

1425 Madison Avenue
New York, NY 10029
United States

Wayne W. Poon

University of California, Irvine - Institute for Memory Impairments and Neurological Disorders ( email )

Irvine, CA
United States

Alison M. Goate

Mount Sinai Health System, Icahn School of Medicine, Nash Department of Neuroscience ( email )

New York, NY
United States

Mount Sinai Health System, Icahn School of Medicine, Ronald M. Loeb Center for Alzheimer's Disease ( email )

New York, NY 10029
United States

Mount Sinai Health System, Icahn School of Medicine, Department of Genetics and Genomic Sciences ( email )

1425 Madison Avenue
New York, NY 10029
United States

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