Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology
Li-Huei Tsai’s fascination with Alzheimer’s disease (AD) began with cloning Cdk5 and its subunit p35 and discovering their role in neuronal migration and morphogenesis. After finding that cleavage of p35 into p25 renders Cdk5 hyperactive and promotes Tau pathology seen in AD, she created an inducible AD mouse model based on p25 expression and used it to investigate AD pathogenesis and identify new therapeutic targets. She showed that Cdk5/p25-related upregulation of HDAC2 blocks neuronal gene expression, leading to synaptic and memory deficits, and that downregulation of HDAC1 increases DNA double stranded breaks (DSB), leading to neurotoxicity. Building on this work, she made the surprising discovery that DSB formation is part of normal neuronal activity and critical for memory formation.
Tsai then teamed up with MIT colleague Kellis Manolis on transcriptomic and epigenomic brain analyses at different neurodegeneration stages. They identified PU.1 as a master regulator of neuroinflammation and key therapeutic target and constructed the first map of gene expression by disease state and brain cell type, revealing sex-specific differences as well as previously unrecognized roles for oligodendrocytes and myelination in AD.
Tsai pioneered the use of patient-derived induced pluripotent stem cell (iPSC) to produce cerebral organoids that model AD pathology. Using CRISPR technology to generate isogenic iPSC lines, she showed that presence of ApoE4 led to lipid accumulation, proinflammatory phenotypes, and hyperexcitability in iPSC-derived brain cells. By combining different iPSC-derived cell types in a 3D matrix, she was able to model the brain blood barrier and dissect how ApoE4 leads to cerebral amyloid angiopathy.
Perhaps her most exciting discovery was the use of non-invasive sensory stimulation to ameliorate AD pathology and symptoms. She showed that stimulation with a 40 Hz flashing light and/or pulsing tone entrained increased gamma power and synchrony and reduced tau and amyloid levels in the brains of AD mice, at least partially mediated by improved glymphatic clearance. Several clinical studies have since shown 40 Hz stimulation to be safe in humans and indicated efficacy against AD.