Cure Alzheimer's Fund: Targeting Breakthrough Research

Research in Dr. Thinakaran's lab investigates mechanisms that regulate Alzheimer's disease β-amyloid (Aβ) production and deposition. Specifically, they study the biology of BACE1 and γ-secretase, the two enzymes that sequentially cleave amyloid precursor protein (APP) to generate Aβ. Recent investigations in their lab center on the regulation of BACE1 and γ-secretase function by post-translational S-palmitoylation, live-cell analysis of dynamic membrane trafficking of BACE1, and the characterization of γ-secretase modulating protein p23. As a post-doctoral fellow, at The Johns Hopkins University School of Medicine Dr. Thinakaran participated in the early characterization of presenilin biology and investigations on how FAD mutations in PS1 affect Aβ production using cell culture and animal models. For over twelve years heI has been leading a group at the University of Chicago, investigating multiple aspects of Alzheimer's disease cell biology including, the physiological and pathological functions of presenilins, regulation of APP trafficking and metabolism, modulation of amyloid production/deposition by post-translational modification of APP secretases and interaction with associated proteins, and the characterization of subcellular sites and membrane microdomains involved in the generation of Aβ peptides.  They have been using an integrated approach that combines hypothesis driven mutagenesis, biochemical characterization, detailed subcellular localization, advanced live cell imaging, and electrophysiology to accomplish our goals. Cultured non-neuronal cells, primary hippocampal neurons, transgenic, knock-out and gene-targeted mice serve as experimental models in the investigation.