Tae-Wan Kim, PhD
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. Several cellular disease models are being used, including mouse embryonic stem (ES) cell-derived neurons as an alternative to primary cortical neurons for small molecule screening and functional genetic analyses. Relevant mouse models are also being utilized.
The first theme of our research is to understand the fundamental biochemical and cellular defects associated with the familial forms of AD, which occur in a small, but significant proportion of AD cases. Mutations in the genes encoding the presenilins (PS1 and PS2) are the most common cause of early-onset FAD and give rise to multiple cellular deficits. Although familial AD (FAD) accounts for a small percentage of all AD cases, at the neuropathological level it is phenotypically indistinguishable from the more common (sporadic) form of AD. Thus, understanding the genotype-to-phenotype transition in presenilin-dependent FAD is likely to shed light on the pathogenesis of the more common, non-familial AD. It has been shown that PS1 or PS2 serve as catalytic components of the γ-secretase complex that is essential for regulated intramembrane proteolysis (RIP) of select transmembrane receptor-like substrates, including APP. At the same time, the presenilins are well-accepted as regulators of calcium and several ion channels via a γ-secretase-independent mechanism. We investigate the molecular basis for the multi-functional nature of the presenilins as regulators of both intracellular ion homeostasis and intramembrane proteolysis. Both γ-secretase-independent and dependent pathogenic mechanisms have been studied in the lab.
The second 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 (synaptic dysfunction). Synaptic dysfunction caused by Aβ has been linked to cognitive decline associated with AD. Molecular, physiological and mouse genetic approaches are currently being used to investigate the hypothesis that Aβ-induced PI(4,5)P2 breakdown is an early and critical event that precedes other Aβ-associated morphological and functional synaptic changes such as loss of dendritic spines and suppression of long-term potentiation (LTP). We are also addressing whether the PI(4,5)P2 pathway can be targeted for novel AD therapeutics. This project is being conducted in close collaboration with the laboratory of Dr. Gilbert Di Paolo.
The goal of third project is to understand how BACE1, one of the key enzymes responsible for Aβ biogenesis, is regulated in neural cells. BACE1 mediates the proteolytic cleavage of β-amyloid precursor protein (APP) and the activity/levels of BACE1 are elevated in brains of AD mouse models as well as in postmortem AD brain tissue. We have conducted a high throughput cell-based assay and identified small molecules that can modulate BACE1 function via either a direct or indirect mechanism. Using these chemical probes, our laboratory is trying to understand the mechanism of BACE1 regulation by identifying cellular target(s) of these novel chemical modulators of BACE1. Furthermore, some of the small molecule hits are being developed as therapeutic candidates for the treatment of AD. Complementary to the chemical biology approach, biochemical experiments to isolate the BACE1-haboring molecular complex have been conducted. Several BACE1-associated proteins, including members of the sorting nexin and sortilin families of protein trafficking modulators, have been identified. The function and pathological relevance of these proteins are being investigated.
Berman DE, Dall’Armi C, Voronov SV, McIntire LB, Zhang H, Moore AZ, Staniszewski A, Arancio O, Kim T-W*, and Di Paolo G*. (2008). Oligomeric amyloid β-peptide disrupts phosphatidylinositol-4,5-bisphosphate metabolism. Nature Neurosci. 11, 547-554.
Landman N, Jeong SY, Shin SY, Voronov SV, Serban G, Kang MS, Park M-K, Di Paolo G, Chung S, and Kim T-W. (2006) Presenilin mutations linked to familial Alzheimer’s disease cause an imbalance in phosphatidylinositol-4,5-bisphosphate metabolism. Proc. Natl. Acad. Sci. USA.103, 19524-19529.
Small SA, Kent K, Pierce A, Leung C, Kang MS, Okada H, Honig L, Vonsattel J-P, and Kim T-W. (2005) Model-guided microarray implicates the retromer trafficking complex in Alzheimer’s disease. Ann Neurol. 58, 909-919.
Yoo AS, Cheng I, Chung S, Grenfell TZ, Lee H, Pack-Chung E, Handler M, Shen J, Xia W, Tesco G, Saunders AJ, Ding K, Frosch MP, Tanzi RE, and Kim T-W. (2000) Presenilin-mediated modulation of capacitative calcium entry. Neuron 27, 561-572.