Seminar lecture series from leaders in the field.

Li-Huei Tsai, PhD

Director, The Picower Institute for Learning and Memory

Co-Director, Alana Down Syndrome Center

Professor, Department of Brain and Cognitive Sciences

Senior Associate Member, Broad Institute
Massachusetts Institute of Technology

Uncovering the role of Alzheimer’s disease risk genes using stem cells and human brains

Abstract: Alzheimer’s disease (AD) is a debilitating brain disorder, with staggering human and financial cost. While genomic studies increasingly identify genetic risk alleles that correlate with AD, there is still no clear picture of the underlying molecular and cellular mechanism(s).  My lab uses a multi-prone approach to understand how cellular, molecular and brain circuit dysfunctions contribute to AD.  We recently reported the first single-cell transcriptomic analysis of the prefrontal cortex to decipher the cell types and molecular pathways impacted by AD (Mathys et al. 2019, Nature). In addition to known AD affected pathways, we found prominent alteration of oligodendrocyte lineage cells, broad cell type specificity of gene expression alterations, and association of pathology with cell-type specific up- or down-regulation. Moreover, we found that cells from female brains are over-represented in disease-associated subpopulations and that transcriptional responses were substantially different between sexes in several cell types including oligodendrocytes.  Together, these observations highlighted the power and utility of single-cell resolution studies for brain disease research. This has motivated us to expand our single-cell investigation of AD, including additional brain regions and risk genotypic backgrounds. 

To validate the new hypotheses generated from single cell-level analysis, we used patient derived induced pluripotent stem cells (iPSCs) to model disease risk genes and pathology.  Using human iPSC-derived astrocytes, brain endothelial cells and pericytes, we recreate the human blood brain barrier in vitro (iBBB), creating a highly tractable model that recapitulates key anatomical and physiological properties of the BBB. Using isogenic ApoE3 and ApoE4 iPSC lines to generate iBBBs, we find amyloid accumulation on the iBBB, and that APOE4 iBBBs exhibit significantly more amyloid accumulation than APOE3 iBBBs.  Through combinatorial experiments, we pinpoint the causal cells through which APOE4 predisposes cerebral amyloid angiopathy (CAA), a condition seen in a large proportion of AD patients.  We identify the pathways underlying the accumulation of amyloid along the iBBB and find that inhibiting these pathways with FDA-approved drugs prevent the build-up of amyloid in APOE4 iBBBs.  We are currently leveraging the isogenic ApoE iPSC lines, and human single cell transcriptomic data to investigate how ApoE4 impacts other brain cell types to predispose the development of AD pathology and symptoms.

The Buck Distinguished Lecture Series is made possible through a generous donation from the Donald Richard Stephens Charitable Foundation