Doo Yeon Kim, Ph.D.

Assistant Professor of Neurology, Harvard Medical School; Assistant in Neurology, Genetics and Aging Research Unit, Massachusetts General Institute for Neurodegenerative Diseases, Department of Neurology, Massachusetts General Hospital

 

Dr. Kim has been studying pathogenic mechanisms of Alzheimer’s disease (AD) for more than 16 years. He and his team investigated physiological and pathological functions of BACE1 and presenilin/gamma secretase, two key enzymes that regulate generation of amyloid beta, a major pathogenic molecule associated with AD. Dr. Kim and his colleagues characterized four novel presenilin/gamma secretase substrate proteins and BACE1 substrate proteins that explain how BACE1 regulates neuronal activity under physiological conditions (Kim et al., Nat. Cell. Biol., 2007). Excessive amounts of BACE can disrupt the neuronal activity, making nerve cells more vulnerable to aberrant firing and perhaps seizures, which may explain the higher risk of seizures in Alzheimer’s patients. Recently, Dr. Kim’s lab, together with Dr. Rudy Tanzi’s, developed an innovative three-dimensional (3D) human stem cell culture model of AD (Choi et al., Nat., 2014). By cultivating genetically modified human neural stem cells in a 3D gel system, they were able to recapitulate key events of AD pathology, including amyloid beta plaques and neurofibrillary tangles (NFTs) for the first time. This unique human neural cell culture model can be used for large-scale, high-throughput screening for novel therapeutic targets, which is not feasible in the current AD mouse models. Kim’s “Alzheimer’s in a Dish” model has been listed as one of “10 Breakthrough Technologies of 2015” by “MIT Technology Review,” and it also won the 2015 Smithsonian American Ingenuity Award (Drs. Kim and Tanzi). 

 

Funded Research

Project Description Researchers Funding
3-D Neural Core/High-Throughput Drug Screening for Alzheimer’s Disease Using 3-D Human Neural Culture Systems

The “beta-amyloid cascade hypothesis” of Alzheimer's disease (AD) has provided a major framework for AD drug discovery and has led to many current clinical trials. However, to date, no single in vitro or in vivo AD model has been able to recapitulate the presumed patient pathophysiology: beta-amyloid deposition directly leads to tangles and neurodegeneration. Recently, we created a novel three­ dimensional (3-D) human neural cell culture model of AD using genetically engineered human neural stem cells.

2015 to 2016

$800,000
Generation of Neural Progenitor Cells Overexpressing Alzheimer’s Disease Genes with Familial Mutations and Analysis of Pathological Changes of Alzheimer’s Cells in Vivo

We seek to evaluate the impact of candidate AD drugs on Abeta and tau pathology in human cellular AD models. In collaboration with Dr. Tanzi’s laboratory (Massachusetts General Hospital), we will test the impact of select candidate AD drugs on both Abeta and tau pathology in the 30 human neural cell culture models developed in Aim 4. In the first year, we found that SGSM41i, a candidate AD drug designed to specifically decrease the toxic Abeta42 generation, decreases not only the Abeta plaques but also the tau pathology in the 30 human cellular AD models.

2014
$100,000
Stem Cell Consortium

Stem cells are the least mature cells in the body. Because these cells are so immature, they can be treated with a defined cocktail of factors and, depending on which factors are used and in what sequence, those factors can cause maturation of cells along discrete cell types. With a new tool called induced pluripotent stem cells, it now is possible to take skin cells from adults and return them to this immature state. By redirecting skin cells from Alzheimer’s patients and turning them into nerve cells, we are able to study adult Alzheimer’s neurons (nerve cells) in the lab.

2013
$600,000
Alzheimer Disease Models Based on Human Neural Progenitor Cells

The goal of this project is to develop genetically modified human neural progenitor cells that can replicate Alzheimer’s disease pathology in in vitro and in vivo conditions in order to develop and test Alzheimer disease drugs in human brain cells.

2011
$100,000

Selected Publications

These published papers resulted from Cure Alzheimer’s Fund support.
Steven L. Wagner, Kevin D. Rynearson, Steven K. Duddy, Can Zhang, Phuong D. Nguyen, Ann Becker, Uyen Vo, Deborah Masliah, Louise Monte, Justin B. Klee, Corinne M. Echmalian, Weiming Xia, Luisa Quinti, Graham Johnson, Jiunn H. Lin, Doo Y. Kim, William C. Mobley, Robert A. Rissman, Rudolph E. Tanzi, Pharmacological and Toxicological Properties of the Potent Oral gamma-Secretase Modulator BPN-15606, Journal Of Pharmacology And Experimental Therapeutics, 362(1), Jul 2017, 31-44
Carla D'Avanzo, Jenna Aronson, Young Hye Kim, Se Hoon Choi, Rudolph E. Tanzi and Doo Yeon Kim, Alzheimer's in 3D culture: Challenges and perspectives, BioEssays, 37(10), October 2015, 1139–1148
Young Hye Kim, Se Hoon Choi, Carla D'Avanzo, Matthias Hebisch, Christopher Sliwinski, Enjana Bylykbashi, Kevin J Washicosky, Justin B Klee, Oliver Brüstle, Rudolph E Tanzi & Doo Yeon Kim, A 3D human neural cell culture system for modeling Alzheimer’s disease, Nature Protocols, 10(7), June 2015, 985–1006
Carla D’Avanzo, Christopher Sliwinski, Steven L. Wagner, Rudolph E. Tanzi, Doo Yeon Kim, and Dora M. Kovacs, γ-Secretase modulators reduce endogenous amyloid β42 levels in human neural progenitor cells without altering neuronal differentiation, The FASEB Journal, 29(8), 22 April 2015, 3335-3341
Jaehong Suh, Se Hoon Choi, Donna M. Romano, Moira A. Gannon, Andrea N. Lesinski, Doo Yeon Kim, Rudolph E. Tanzi, ADAM10 Missense Mutations Potentiate β-Amyloid Accumulation by Impairing Prodomain Chaperone Function, Neuron, 80(2), Oct 16, 2013, 385–401