The aim of my research is to study the cellular and molecular pathways involved in the pathogenesis of Alzheimer’s disease (AD). More specifically, my focus is to understand how G protein-coupled receptors (GPCRs) and β-arrestins regulate the amyloid pathway, synaptic plasticity and cognition, and to determine how to therapeutically modulate GPCR/β-arrestin-biased signaling in AD and other neurological disorders. I hypothesize that the β-arrestins provide a putative basis to understand the link between GPCRs and Aβ generation through regulation of the γ-secretase complex and will provide insight into the pathophysiology of GPCR dysfunction in AD and a novel therapeutic avenue for intervention in AD. Consequently, I have adopted two approaches to address my research questions: (1) a focused approach aimed at understanding the molecular, cellular and physiological role of GPR3 and β-arrestin 2 in synaptic function and cognition and regulation of γ-secretase activity, Aβ accumulation and Aβ-mediated synaptotoxicity and (2) a broad approach aimed at attaining a more extensive understanding of the GPCR/β-arrestin network in the brain and in regulation of Aβ generation and the γ-secretase complex under physiological and pathophysiological conditions. By integrating mouse genetics with cellular and biochemical techniques, electrophysiology and behavioral studies, and optogenetic tools, I hope to achieve a greater understanding of the mechanism(s) regulating GPCR and β-arrestin synaptic function and cognition in AD.
Summer Undergraduate Research Program
Huang Y, Thathiah A. Regulation of neuronal communication by G protein-coupled receptors. FEBS Lett. 2015 Jun 22;589(14):1607-19.
Thathiah A, Horré K, Snellinx A, Vandewyer E, Huang Y, Ciesielska M, De Kloe G, Munck S, De Strooper B. β-arrestin 2 regulates Aβ generation and γ-secretase activity in Alzheimer's disease. Nat Med. 2013 Jan;19(1):43-9.
Thathiah A, De Strooper B. The role of G protein-coupled receptors in the pathology of Alzheimer's disease. Nat Rev Neurosci. 2011 Feb;12(2):73-87.
Thathiah A, De Strooper B. G protein-coupled receptors, cholinergic dysfunction, and Abeta toxicity in Alzheimer's disease. Sci Signal. 2009 Oct 20;2(93):re8.
Thathiah A, Spittaels K, Hoffmann M, Staes M, Cohen A, Horré K, Vanbrabant M, Coun F, Baekelandt V, Delacourte A, Fischer DF, Pollet D, De Strooper B, Merchiers P. The orphan G protein-coupled receptor 3 modulates amyloid-beta peptide generation in neurons. Science. 2009 Feb 13;323(5916):946-51.