Abnormally aggregating proteins in cerebral brain tissues during the course of neurodegenerative disorders Despite evidence for a pathogenic role of amyloid plaques and associated neuronal dystrophy, it has become apparent in recent years that soluble, non-fibrillar Amyloid-Beta assemblies, also called Abeta oligomers, are more critical than plaque load in the pathogenesis of Alzheimer's disease-related neuronal dysfunction and memory impairment. However, the exact mechanism by which these multimeric forms are able to alter brain and neuronal function remains to be identified. Due to their size and presence in the extracellular space, our laboratory is examining whether and how Abeta oligomers can interact at neuronal plasma membranes with specific receptors involved in the cellular form of memory called long-term potentiation by combining biochemical and functional assays. In addition, since Abeta has been suggested in 2001 to influence the formation of neurofibrillary tangles, composed of hyperphosphorylated tau proteins, our group also focuses on examining whether soluble Abeta oligomers represent the missing link between tau and amyloid pathologies in Alzheimer's disease, using novel bigenic mice expressing the full human tau gene and APP, the precursor protein of Abeta. We investigate the effect of short- and long-term exposures of soluble Abeta oligomers on tau biochemistry, cellular localization and tau interaction with other microtubule-associated proteins by integrating in vitro and in vivo approaches using newly generated fluorescent protein-tagged knock-in transgenic mice crossed with transgenic mouse models of AD.
