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Publications of the Week

Cholesterol and Matrisome Pathways Dysregulated in Astrocytes and Microglia

By July 5, 2022No Comments

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This week we profile a recent publication in Cell from Dr. Julia TCW (pictured)
at Boston University School of Medicine.

Can you provide a brief overview of your lab’s current research focus?

Dr. Julia TCW received a Ph.D. and A.M. in Molecular and Cellular Biology from Harvard University with research studies in induced pluripotent stem cell (iPSC) reprogramming in the Department of Stem Cell and Regenerative Biology. She then persued her postdoctoral research in the Department of Neuroscience, Ronald M. Loeb Center for Alzheimer’s Disease, Department of Genetics and Genomic Sciences at Icahn School of Medicine at Mount Sinai, New York with a research focus of the development of iPSC models and study Alzheimer’s disease (AD) genetics. She achieved Druckenmiller Fellowship award from New York Stem Cell Foundation and K, U and R awards from NIH-NIA.

Dr. TCW’s laboratory is aiming at human induced pluripotent stem cell therapeutics. There are two main goals; 1) Deciphering functional mechanisms of Alzheimer’s disease (AD) genetics using in vitro iPSCs and in vivo iPSC/mouse Chimera models and 2) Developing in vitro model systems of human brain for drug screen.

  • Much of the research focuses on the effects of AD genetic risks, especially Apolipoprotein E4 (APOE4), the most significant risk factor for late-onset AD on human brain cell types. The lab uses the forward genetic, unbiased multi-Omics computational (bioinformatics) approach to uncover pathways and network defects of AD genetic risks and demonstrate molecular mechanisms of the risk factors in CNS cell types derived from CRISPR/Cas9 genome-edited isogenic and population iPSCs. They develop novel computational pipelines to identify molecular and network drivers and integrate genetics and transcriptomics/proteomics for a functional genomic study. In vitro and in vivo work have been focused on efferocytosis, lipid metabolism, matrisome and inflammation in pure human microglia, astrocytes and organoids (multiple brain cell types as a whole) associated with AD genetic risks. Further, the lab is also collaborating with the industry to find a drug target for AD therapeutics.
  • The lab has developed multiple novel CNS cell type protocols including astrocytes, microglia, pericytes, neural progenitors and glutamatergic neurons and continuously put our effort to advance the 2D models to 3D human brain model to establish efficient platforms for drug screen.

What is the significance of the findings in this publication?

The main finding of the paper is deciphering the strongest risk factor for late-onset Alzheimer’s disease (AD) called Apolipoprotein E4 (APOE4) in human brain cells. We found that 1) human genetic background inherited with APOE4 is unique to APOE4 patients and 2) human glial cell types including astrocytes and microglia have human-specific dysregulation in lipid metabolism that is not observed in mouse models and induce enriched matrix and inflammation when astrocytes communicated with neurons. To sum, two important novel aspects are, there are more than just APOE4 mutation, which is APOE nearby genetic region called haplotype to increase disease risk, and the mechanistic defects due to APOE4 are unique to human cells. 

What are the next steps for this research?

Further interrogate the target identifications in cholesterol and matrisome pathways in glia and reverse the phenotype.

If you’d like us to mention your funding sources, please list them.

NIH NIA K01AG062683
New York Stem Cell Foundation (NYSCF) (Drunkenmiller fellowship)


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