Li-Huei Tsai

Li-Huei Tsai (Chinese: 蔡立慧) is a neuroscientist and the director of the Picower Institute for Learning and Memory in the Department of Brain and Cognitive Sciences at the Massachusetts Institute of Technology.

Li-Huei Tsai
Alma materUniversity of Texas Southwestern Medical Center
Scientific career
FieldsNeuroscience
Institutions
Doctoral advisorEd Harlow
Doctoral studentsGentry Patrick
Websitetsailaboratory.mit.edu/li-huei-tsai/

She is known for her work on neurological disorders that affect learning and memory, particularly for her research on Alzheimer’s disease and the role of CDK5 and chromatin remodeling in the progression of the disease. Additionally, her laboratory has innovated numerous applications of induced pluripotent stem cells for in vitro modeling of neurological diseases.[1]

Education and career

Tsai was born and raised in Taiwan. In 1984, she received a fellowship to pursue a master's degree in veterinary medicine at the University of Wisconsin-Madison.[2] After attending a series of lectures delivered by Nobel Prize laureate and cancer researcher Howard Temin, she developed an interest in molecular cancer research. Tsai earned her PhD in 1990 from the University of Texas Southwestern Medical Center. In 1991, Tsai joined the laboratory of Ed Harlow at the Cold Spring Harbor Laboratory and then the Massachusetts General Hospital Cancer Center. In 1994, Tsai joined the faculty in the Department of Pathology at Harvard Medical School. She moved to MIT in 2006.[3] She was appointed director of the Picower Institute for Learning and Memory in 2009[4] and is a founding member of MIT's Aging Brain Initiative.[5]

Research

In the Harlow laboratory, Tsai studied cyclin-dependent kinases in order to identify their role in cell division. Tsai became interested in CDK5, which she found was not only inactive in cancer cells, but inactive in all other tissue cells except for the brain.[6] She also found that Cdk5 requires p35 to be active.[7]

After moving to Harvard Medical School, she began to investigate the function of CDK5 and p35. Tsai found that mice lacking p35 displayed cortical lamination defects and were prone to seizures,[8] and that CDK5-p35 activity was essential for neurite outgrowth during neuronal differentiation.[9] Tsai also discovered that while Cdk5 activity is essential to proper brain development and function, overexpression of Cdk5 was associated with Alzheimer’s disease. Tsai observed that a truncated version of p35 called p25 accumulated in diseased or damaged brain tissue in mice and in tissue samples from deceased Alzheimer’s patients.[10][11] In an experiment with genetically-engineered mice, Tsai found that increased expression of CDK5 led to the development of Alzheimer’s-like symptoms such as a decline in learning and cognition, profound neural loss in the forebrain, and that amyloid plaques developed within weeks.[12]

After moving to MIT in 2006, Tsai began to investigate how to ameliorate or reverse Alzheimer’s symptoms. In a 2007 study, Tsai trained mice to find and remember a platform submerged in a murky pool. When she induced Alzheimer’s-like symptoms, the mice could no longer find the platform; however, after spending some time in an enriched environment, those same mice could locate platform immediately, indicating their memories had returned. Tsai was able to replicate the same effects as the enriched environment by treating the mice with a drug that inhibited a chromatin-remodeling class of enzymes called histone deacetylases, or HDACs.[13][14] In later studies, Tsai showed that HDAC2 creates an epigenetic blockade of genes that regulate structural and synaptic plasticity[15] and that some cognitive function could be restored by inhibiting HDAC2 activity.[16][17]

Tsai has elucidated the role of structural and epigenetic mechanisms in Alzheimer's disease, showing in two 2015 studies that the DNA breakage necessary to learning was also responsible for cognitive decline, due to decline in DNA repair systems with age,[18][19] and that the genetic component of Alzheimer’s primarily affects the regulatory circuitry of immune processes, rather than neuronal processes as expected.[20][21] In 2016, Tsai demonstrated that visual stimulation of mice with an LED flashing at 40 hertz substantially reduces the beta amyloid plaques associated with Alzheimer’s disease, likely by inducing gamma oscillations.[22][23] In more recent work, Tsai has created a lab-engineered model of the Blood-Brain Barrier to investigate how Alzheimer disease risk genes, namely APOE, contribute to breakdown of the brain's vasculature.[24]

Awards
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See also
  • Alzheimer's disease research § Research directions
  • Neuroscience of ageing

References
  1. Penney J, Ralvenius WT, Tsai LH (2020). "Modeling Alzheimer's disease with iPSC-derived brain cells". Mol Psychiatry. 25 (1): 148–167. doi:10.1038/s41380-019-0468-3. PMC 6906186. PMID 31391546.CS1 maint: multiple names: authors list (link)
  2. Anna Azvolinsky (2017-11-01). "Flickers of Hope". Retrieved 2019-11-09.
  3. Mone, Gregory. "The Persistence of Memory". MIT Technology Review. Retrieved 2017-03-21.
  4. "Li-Huei Tsai to direct Picower Institute". MIT News. Retrieved 2017-03-21.
  5. "Study finds path for addressing Alzheimer's blood-brain barrier impairment". MIT News. Retrieved 2020-07-12.
  6. Tsai, L. H.; Takahashi, T.; Caviness, V. S.; Harlow, E. (1993-12-01). "Activity and expression pattern of cyclin-dependent kinase 5 in the embryonic mouse nervous system". Development. 119 (4): 1029–1040. ISSN 0950-1991. PMID 8306873.
  7. Tsai, Li-Huei; Delalle, Ivana; Caviness, Verne S.; Chae, Teresa; Harlow, Ed (1994-09-29). "p35 is a neural-specific regulatory subunit of cyclin-dependent kinase 5". Nature. 371 (6496): 419–423. doi:10.1038/371419a0. PMID 8090221.
  8. Chae, Teresa; Kwon, Young T.; Bronson, Roderick; Dikkes, Pieter; Li, En; Tsai, Li-Huei (1997-01-01). "Mice Lacking p35, a Neuronal Specific Activator of Cdk5, Display Cortical Lamination Defects, Seizures, and Adult Lethality". Neuron. 18 (1): 29–42. doi:10.1016/S0896-6273(01)80044-1. PMID 9010203.
  9. Nikolic, M.; Dudek, H.; Kwon, Y. T.; Ramos, Y. F.; Tsai, L. H. (1996-04-01). "The cdk5/p35 kinase is essential for neurite outgrowth during neuronal differentiation". Genes & Development. 10 (7): 816–825. doi:10.1101/gad.10.7.816. ISSN 0890-9369. PMID 8846918.
  10. Patrick, G. N.; Zukerberg, L.; Nikolic, M.; de la Monte, S.; Dikkes, P.; Tsai, L. H. (1999-12-09). "Conversion of p35 to p25 deregulates Cdk5 activity and promotes neurodegeneration". Nature. 402 (6762): 615–622. doi:10.1038/45159. ISSN 0028-0836. PMID 10604467.
  11. Tseng, Huang Chun; Zhou, Ying; Shen, Yong; Tsai, Li Huei (2002-07-17). "A survey of Cdk5 activator p35 and p25 levels in Alzheimer's disease brains". FEBS Letters. 523 (1–3): 58–62. doi:10.1016/s0014-5793(02)02934-4. ISSN 0014-5793. PMID 12123804.
  12. Cruz, Jonathan C.; Tseng, Huang-Chun; Goldman, Joseph A.; Shih, Heather; Tsai, Li-Huei (2003-10-30). "Aberrant Cdk5 activation by p25 triggers pathological events leading to neurodegeneration and neurofibrillary tangles". Neuron. 40 (3): 471–483. doi:10.1016/s0896-6273(03)00627-5. ISSN 0896-6273. PMID 14642273.
  13. Fischer, Andre; Sananbenesi, Farahnaz; Wang, Xinyu; Dobbin, Matthew; Tsai, Li-Huei (2007-05-10). "Recovery of learning and memory is associated with chromatin remodelling". Nature. 447 (7141): 178–182. doi:10.1038/nature05772. ISSN 1476-4687. PMID 17468743.
  14. "Picower-led team pinpoints gene key to Alzheimer's-like reversal". MIT News. Retrieved 2017-03-21.
  15. Gräff, Johannes; Rei, Damien; Guan, Ji-Song; Wang, Wen-Yuan; Seo, Jinsoo; Hennig, Krista M.; Nieland, Thomas J. F.; Fass, Daniel M.; Kao, Patricia F. (2012-03-08). "An epigenetic blockade of cognitive functions in the neurodegenerating brain". Nature. 483 (7388): 222–226. doi:10.1038/nature10849. ISSN 0028-0836. PMC 3498952. PMID 22388814.
  16. "Picower-led team pinpoints gene key to Alzheimer's-like reversal". MIT News. Retrieved 2017-03-21.
  17. Guan, Ji-Song; Haggarty, Stephen J.; Giacometti, Emanuela; Dannenberg, Jan-Hermen; Joseph, Nadine; Gao, Jun; Nieland, Thomas J. F.; Zhou, Ying; Wang, Xinyu (2009-05-07). "HDAC2 negatively regulates memory formation and synaptic plasticity". Nature. 459 (7243): 55–60. doi:10.1038/nature07925. ISSN 1476-4687. PMC 3498958. PMID 19424149.
  18. "DNA breakage underlies both learning, age-related damage". MIT News. Retrieved 2017-03-21.
  19. Madabhushi, Ram; Gao, Fan; Pfenning, Andreas R.; Pan, Ling; Yamakawa, Satoko; Seo, Jinsoo; Rueda, Richard; Phan, Trongha; Yamakawa, Hidekuni (2015-06-18). "Activity-Induced DNA Breaks Govern the Expression of Neuronal Early-Response Genes". Cell. 161 (7): 1592–1605. doi:10.1016/j.cell.2015.05.032. ISSN 0092-8674. PMC 4886855. PMID 26052046.
  20. "Epigenomics of Alzheimer's disease progression". MIT News. Retrieved 2017-03-21.
  21. Gjoneska, Elizabeta; Pfenning, Andreas R.; Mathys, Hansruedi; Quon, Gerald; Kundaje, Anshul; Tsai, Li-Huei; Kellis, Manolis (2015-02-19). "Conserved epigenomic signals in mice and humans reveal immune basis of Alzheimer/'s disease". Nature. 518 (7539): 365–369. doi:10.1038/nature14252. ISSN 0028-0836. PMC 4530583. PMID 25693568.
  22. Shukla, Varsha; Seo, Jinsoo; Binukumar, B. K.; Amin, Niranjana D.; Reddy, Preethi; Grant, Philip; Kuntz, Susan; Kesavapany, Sashi; Steiner, Joseph (2017-01-01). "TFP5, a Peptide Inhibitor of Aberrant and Hyperactive Cdk5/p25, Attenuates Pathological Phenotypes and Restores Synaptic Function in CK-p25Tg Mice". Journal of Alzheimer's Disease. 56 (1): 335–349. doi:10.3233/JAD-160916. ISSN 1875-8908. PMID 28085018.
  23. Roberts, Michelle (2016-12-07). "'Flashing light therapy' for Alzheimer's". BBC News. Retrieved 2017-03-21.
  24. "Study finds path for addressing Alzheimer's blood-brain barrier impairment". MIT News. Retrieved 2020-07-12.
  25. "Glenn Foundation for Medical Research Glenn Award for Research in Biological Mechanisms of Aging". glennfoundation.org. Retrieved 2017-03-21.
  26. "Two MIT scientists elected to the Institute of Medicine". MIT News. Retrieved 2017-03-21.
  27. "6 from MIT named AAAS fellows". MIT News. Retrieved 2017-03-21.
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