Markku Kurkinen
Professor Wayne State University School of Medicine USA
Title: Alzheimer's drug discovery: targeting synaptic glutamate signaling
Biography:
Born October 8, 1949, Mikkeli, Finland. 1979 PhD, University of Helsinki, Finland. 1980-1983 postdoctoral work with Brigid Hogan, Imperial Cancer Research Fund (ICRF), Mill Hill London, UK. 1984-1985 Assistant Professor, University of Medicine and Dentistry of New Jersey (UMDNJ), Rutgers Medical School, Piscataway, New Jersey, USA. 1985-1992 Associate Professor, Chief of Connective Tissue Research, UMDNJ, Robert Wood Johnson Medical School (formerly Rutgers Medical School), Piscataway, New Jersey, USA. 1992 - Professor, Wayne State University School of Medicine, Detroit, Michigan, USA. Published work on Matrix Biology,molecular cloning, and gene regulation. Present researchinterests in novel drug discovery methods, targeting astrocyte regulation of synaptic glutamate signaling in developmental and neuropsychiatric brain disorders.
Abstract:
Glutamate, a non-essential amino acid, is the signaling molecule of neurons. Glutamate is neurotoxic. As soon as the glutamate signaling starts it is stopped in 0.1-2 ms by astrocytes, which take up and clear glutamate from synapses. This prevents too much glutamate causing impaired synaptic function and loss of neurons. Astrocytes make EAAT2 (excitatory amino acid transporter-2), the major glutamate transporter and 1% of brain protein. In Alzheimer dementia, astrocytes express less EAAT2. In experimental mouse models of Alzheimer, increasing EAAT2 expression slows dementia progression. To discover drugs that can activate EAAT2 in glutamate uptake, I describe a simple assay that targets the EAAT2 protein reconstituted in liposomes and measures glutamate uptake with fluorescent Oxonol VI red light. Importantly, by direct targeting the EAAT2 protein in liposomes, the assay should limit ‘off-targeting’ of drugs and adverse events, which are the main problems in Alzheimer’s drug discovery and clinical development.