Cholesterol and matrisome pathways dysregulated in astrocytes and microglia

Julia Tcw; Lu Qian; Nina H Pipalia; Michael J Chao; Shuang A Liang; Yang Shi; Bharat R Jain; Sarah E Bertelsen; Manav Kapoor; Edoardo Marcora; Elizabeth Sikora; Elizabeth J Andrews; Alessandra C Martini; Celeste M Karch; Elizabeth Head; David M Holtzman; Bin Zhang; Minghui Wang; Frederick R Maxfield; Wayne W Poon; Alison M Goate

doi:10.1016/j.cell.2022.05.017

Cholesterol and matrisome pathways dysregulated in astrocytes and microglia

Cell. 2022 Jun 23;185(13):2213-2233.e25. doi: 10.1016/j.cell.2022.05.017.

Authors

Julia Tcw¹, Lu Qian², Nina H Pipalia³, Michael J Chao⁴, Shuang A Liang⁵, Yang Shi⁶, Bharat R Jain⁵, Sarah E Bertelsen⁷, Manav Kapoor⁸, Edoardo Marcora⁹, Elizabeth Sikora⁷, Elizabeth J Andrews¹⁰, Alessandra C Martini¹⁰, Celeste M Karch¹¹, Elizabeth Head¹², David M Holtzman⁶, Bin Zhang¹³, Minghui Wang¹⁴, Frederick R Maxfield³, Wayne W Poon¹⁵, Alison M Goate¹⁶

Affiliations

¹ Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA 02118, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Nash Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: juliatcw@bu.edu.
² Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA 02118, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Nash Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
³ Department of Biochemistry, Weill Cornell Medical College, New York, NY 10065, USA.
⁴ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Nash Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Sanofi US, Cambridge, MA 02141, USA.
⁵ Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA 92697, USA.
⁶ Department of Neurology, Washington University School of Medicine, St. Louis, MO 63108, USA; Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO 63108, USA.
⁷ Nash Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
⁸ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Nash Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Regeneron Pharmaceuticals, Inc., Tarrytown, NY 10591, USA.
⁹ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Nash Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
¹⁰ Department of Pathology and Laboratory Medicine, University of California, Irvine, Irvine, CA 92697, USA; Center for the Neurobiology of Learning and Memory, University of California, Irvine, Irvine, CA 92697, USA.
¹¹ Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO 63108, USA; Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63108, USA.
¹² Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA 92697, USA; Department of Pathology and Laboratory Medicine, University of California, Irvine, Irvine, CA 92697, USA; Center for the Neurobiology of Learning and Memory, University of California, Irvine, Irvine, CA 92697, USA.
¹³ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Mount Sinai Center for Transformative Disease Modeling, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
¹⁴ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Mount Sinai Center for Transformative Disease Modeling, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
¹⁵ Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA 92697, USA; NeuCyte, Inc., Mountain View, CA 94043, USA.
¹⁶ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Nash Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: alison.goate@mssm.edu.

Abstract

The impact of apolipoprotein E ε4 (APOE4), the strongest genetic risk factor for Alzheimer's disease (AD), on human brain cellular function remains unclear. Here, we investigated the effects of APOE4 on brain cell types derived from population and isogenic human induced pluripotent stem cells, post-mortem brain, and APOE targeted replacement mice. Population and isogenic models demonstrate that APOE4 local haplotype, rather than a single risk allele, contributes to risk. Global transcriptomic analyses reveal human-specific, APOE4-driven lipid metabolic dysregulation in astrocytes and microglia. APOE4 enhances de novo cholesterol synthesis despite elevated intracellular cholesterol due to lysosomal cholesterol sequestration in astrocytes. Further, matrisome dysregulation is associated with upregulated chemotaxis, glial activation, and lipid biosynthesis in astrocytes co-cultured with neurons, which recapitulates altered astrocyte matrisome signaling in human brain. Thus, APOE4 initiates glia-specific cell and non-cell autonomous dysregulation that may contribute to increased AD risk.

Keywords: APOE; Alzheimer; astrocytes; cholesterol; genetic heterogeneity; haplotypes; iPSC disease modeling; inflammation; matrisome; microglia.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Alzheimer Disease* / genetics
Alzheimer Disease* / metabolism
Animals
Apolipoprotein E3 / genetics
Apolipoprotein E3 / metabolism
Apolipoprotein E4 / genetics
Apolipoprotein E4 / metabolism
Apolipoproteins E / genetics
Apolipoproteins E / metabolism
Astrocytes / metabolism
Cholesterol / metabolism
Humans
Induced Pluripotent Stem Cells* / metabolism
Mice
Microglia / metabolism

Substances

Apolipoprotein E3
Apolipoprotein E4
Apolipoproteins E
Cholesterol

Abstract

Publication types

MeSH terms

Substances

Grants and funding