The major goal of our laboratory is to understand the molecular basis of Alzheimer's disease (AD) using a multidisciplinary approach based on molecular, cellular and chemical biology. We are also conducting translational research aimed at the discovery and pre-clinical development of novel therapies for AD. We extensively use mouse embryonic stem (ES) cell-derived neurons as an alternative to primary cortical neurons for small molecule screening and target validation studies. The first subject of our research is to identify molecular factors controlling biogenesis and synaptic action of amyloid β-peptide (Aβ), a pathogenic agent in AD. Our recent studies reveal that alterations in phosphatidyl-4,5-bisphosphate [known as PI(4,5)P2], a phosphoinositide lipid that controls several essential neural functions, contributes to the biochemical and cellular defects associated with AD. Specific emphasis has been given to the role of PI(4,5)P2 in Aβ-induced impairments in synaptic plasticity. The goal of second project is to understand how BACE1 (Aβ-generating enzyme) is regulated in neural cells. We have conducted a high throughput cell-based assay and identified small molecules that can modulate BACE1 function via a novel mechanism. We are currently trying to understand the mechanism of BACE1 regulation by identifying cellular target(s) of these chemical probes.
Finan GM, Okada H, Kim T-W.
BACE1 retrograde trafficking is uniquely regulated by the cytoplasmic domain of sortilin submitted :. (2010)
Okada H, Zhang W, Peterhoff C, Hwang JC, Nixon RA, Kim T-W.
Proteomics identification of sorting nexin 6 as a negative regulator of BACE1-mediated APP processing. FASEB J. 24:2783-94. (2010)
Berman DE, Dall’Armi C, Voronov SV, McIntire LB, Zhang H, Moore AZ, Staniszewski A, Arancio O, Kim T-W#, and Di Paolo G#.
Oligomeric amyloid β-peptide disrupts phosphatidylinositol-4,5-bisphosphate metabolism Nature Neurosci 11:547-54. (2008)
Landman N, Jeong SY, Shin SY, Voronov SV, Serban G, Kang MS, Park M-K, Di Paolo G, Chung S, and Kim T-W.
Presenilin mutations linked to familial Alzheimer’s disease cause an imbalance in phosphatidylinositol-4,5-bisphosphate metabolism. Proc. Natl. Acad. Sci. USA. 103:19524-29. (2006)
Small SA, Kent K, Pierce A, Leung C, Kang MS, Okada H, Honig L, Vonsattel J-P, and Kim T-W.
Model-guided microarray implicates the retromer trafficking complex in Alzheimer’s disease. Ann Neurol. 58:909-19. (2005)