Choi Lab
Overview
Alzheimer’s disease (AD) robs millions of people of their memories, independence, and identity — yet its underlying biology remains incompletely understood, and no disease‑modifying treatment exists. Our laboratory pursues three interconnected research programs: harnessing the brain’s regenerative capacity through adult‑born neurons, building human “brain‑in‑a‑dish” models to study disease mechanisms, and decoding how exercise protects against cognitive decline.
Research Projects
Regenerating the Brain’s Memory Center
The adult brain can generate new neurons throughout life — a process known as adult hippocampal neurogenesis (AHN). Our lab was the first to demonstrate that impairment of AHN is a primary driver of Alzheimer’s pathology, rather than a downstream consequence (Choi et al., Science, 2018). We also showed that enhancing AHN — particularly when paired with elevated levels of the growth factor BDNF — can modify the course of disease.
We are now uncovering the mechanisms by which AHN builds up cognitive and synaptic resilience as well as the cellular and molecular switches that regulate AHN, both cell‑autonomously and through interactions with surrounding neurogenic niche cells.
A Human Brain in a Dish
To study human Alzheimer’s biology directly, we engineered a groundbreaking platform: human neural stem cells grown in a three‑dimensional culture system that, for the first time, spontaneously forms the amyloid plaques and neurofibrillary tangles that define AD (Choi et al., Nature, 2014). This landmark achievement has been adopted worldwide and continues to accelerate drug discovery. We are now expanding this platform by incorporating neurovascular and meningeal lymphatic components, creating an even more faithful replica of the human brain environment. This next‑generation system allows us to investigate how the brain’s waste‑clearance pathways — including the blood–brain barrier (BBB) and lymphatic networks — break down in AD.
Exercise as Medicine
Our lab identified a key molecular mechanism by which exercise protects the brain. The hormone irisin, released during physical activity, reduces amyloid‑β (Aβ) burden by triggering astrocytes to release the Aβ‑degrading enzyme neprilysin through ERK–STAT3 downregulation (Kim et al., Neuron, 2023). We also identified integrin αV/β5 as the astrocytic receptor through which irisin acts. These discoveries lay the foundation for developing irisin‑mimetic drugs — a potential new class of Alzheimer’s therapeutics that could deliver the cognitive benefits of exercise in a pill.
Our Vision
Our progress reflects both strong independent research and extensive collaborations with leading experts. Our ultimate goal is to uncover the pathological mechanisms of AD and to develop regenerative therapies by identifying novel, druggable targets to treat cognitive decline in aging and neurodegenerative disorders. We aim to achieve these objectives through meaningful collaborations and, ultimately, to share our scientific discoveries in ways that benefit patients, families, and society.
Research Team
Se Hoon Choi
Principal Investigator
Dr. Choi’s research focuses on defining how adult‑born neurons (adult hippocampal neurogenesis, AHN) promote cognitive and synaptic resilience; identifying the cellular and molecular switches that regulate AHN; developing 3D human neural cell culture models to elucidate Alzheimer’s disease (AD) mechanisms and uncover therapeutic targets; and delineating the molecular pathways through which exercise confers neuroprotection in AD. His overarching goal is to identify druggable targets to prevent or treat cognitive decline in aging and neurodegenerative disease.
Dr. Choi has extensive expertise in AD, AHN, and advanced 3D neural culture systems, supported by a broad background in neurobiology. His research productivity reflects both strong independent scholarship and deep collaborative engagement with leading experts, to whom he contributes specialized technical and conceptual expertise. Email: Choi.SeHoon@mgh.harvard.edu
Ryan Castro
Post-doctoral research fellow
Dr. Ryan Castro is originally from Shirley, Massachusetts and received his PhD from Brown University in 2022. His thesis work focused on describing age-related changes in alpha motor neurons and microglia in the spinal cord, and their potential contribution to age-related motor dysfunction. Dr. Castro is now a postdoctoral fellow in the Genetics and Aging Research Unit working directly under Dr. Se Hoon Choi. His postdoctoral work, which is supported by an F99/K00 fellowship from the National Institute on Aging, is focused on uncovering mechanisms by which microglia regulate adult hippocampal neurogenesis in health and in aging/disease. In his free time, Dr. Castro enjoys spending time with his wife, watching Boston sports teams, and playing golf. Email: rwcastro@mgh.harvard.edu
Xun Wang
Post-doctoral research fellow
Dr. Wang’s research goal is to develop physiologically relevant 3D human brain models in microfluidic systems to dissect molecular and biomechanical mechanisms underlying neurodegenerative diseases (NDs) and accelerate the discovery of new therapeutics for NDs. He received a BS in mechanical engineering and automation and a BA in German from Shanghai Jiao Tong University in 2014, and a PhD in mechanical engineering from Columbia University in 2021. Email: xwang120@mgh.harvard.edu
Nadia Sbisa
Research technician
Nadia Sbisa graduated in 2026 from University of Michigan with a B.S. in Biochemistry and Philosophy. She now works as a technician in the Choi lab focusing on screening therapeutics targeting Alzheimer’s disease.
Alyssa Cai
Undergraduate student
Isabel Maria Morento Rivas
Undergraduate student
August Vermeire
Intern student
Publications
- Kim EH, Kim HW, Jedrychowski MP, Bakiasi G, Park J, Kruskop J, Choi YJ, Kwak SS, Quinti L, Kim DY, Wrann CD, Spiegelman BM, Tanzi RE, Choi SH. Irisin reduces Amyloid-β by inducing the release of neprilysin from astrocytes following downregulation of ERK-STAT3 signaling. Neuron. 2023; 111, 3619-3633. DOI: 10.1016/j.neuron.2023.08.012. PubMed PMID: 37689059.
- Choi SH, Bylykbashi E, Chatila ZK, Lee SW, Pulli B, Clemenson GD, Kim EH, Rompala A, Oram MK, Asselin C, Aronson J, Zhang C, Miller SJ, Lesinski A, Chen JW, Kim DY, van Praag H, Spiegelman BM, Gage FH, Tanzi RE. Combined adult neurogenesis and BDNF mimic exercise effects on cognition in an Alzheimer's mouse model. Science. 2018 Sep 7;361(6406). DOI: 10.1126/science.aan8821. PubMed PMID: 30190379; PubMed Central PMCID: PMC6149542.
- Choi SH, Kim YH, Hebisch M, Sliwinski C, Lee S, D'Avanzo C, Chen H, Hooli B, Asselin C, Muffat J, Klee JB, Zhang C, Wainger BJ, Peitz M, Kovacs DM, Woolf CJ, Wagner SL, Tanzi RE, Kim DY. A three-dimensional human neural cell culture model of Alzheimer's disease. Nature. 2014 Nov 13;515(7526):274-8. DOI: 10.1038/nature13800. Epub 2014 Oct 12. PubMed PMID: 25307057; PubMed Central PMCID: PMC4366007.
- Salta E, Lazarov O, Fitzsimons CP, Tanzi RE, Lucassen PJ, Choi SH. Adult hippocampal neurogenesis in Alzheimer’s disease: A roadmap to clinical relevance. Cell Stem Cell. 2023 Feb 2;30(2):120-136. doi: 10.1016/j.stem.2023.01.002. PubMed PMID: 36736288; PubMed Central PMCID: PMC10082636.