Mass General Research Institute
Assistant Professor of Neurology
Harvard Medical School
adult stem cells; alzheimer's disease; hippocampus; neurogenesis; regenerative medicine
I have been investigating the pathogenic mechanism(s) of Alzheimer’s disease (AD) and the role of adult-generated neurons in the disease since 1999. The human hippocampus, one of the first areas to degenerate in AD, contains neural stem cells which continue to generate new neurons into old age, a process called adult hippocampal neurogenesis (AHN). AHN is impaired in AD patients. We found that inducing AHN alone did not improve cognition in AD mice, whereas inducing neurogenesis while simultaneously ameliorating the neuronal environment via exercise did (Choi et al., Science 2018). Using genetic or pharmacological treatments that simultaneously induced neurogenesis and increased levels of brain-derived neurotrophic factor (BDNF) mimicked the benefits of exercise on cognition. Inducing both neurogenesis and BDNF may be useful as an AD therapeutic. We also found that the expression of Familial AD (FAD)-linked presenilin 1 (PSEN1) variants regulates AHN in mice and is capable of mitigating the regenerative effects associated with increased activity and environmental enrichment likely through changes in resident microglia and their secreted factors (Choi et al., Neuron 2008). We also developed a human stem cell culture model of AD by cultivating genetically modified human neural stem cells in a three-dimensional (3D) cell culture system. Our 3D culture system successfully recapitulates key events of AD pathology including amyloid β (Aβ) plaques and neurofibrillary tangles (NFTs) for the first time (Choi et al., Nature 2014). This unique strategy for recapitulating AD pathology in a single 3D cell culture model will serve to facilitate the development of more precise human neural cell models for other neurodegenerative disorders.