Sylvain Lesné, PhD, MSci
Associate Professor, Department of Neuroscience
Associate Professor, Department of Neuroscience
Institute for Translational Neuroscience Scholar
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.
Singh, B, Covelo, A, Martell-Martínez, H, Nanclares, C, Sherman, MA, Okematti, E, Meints, J, Teravskis, PJ, Gallardo, C, Savonenko, AV, Benneyworth, MA, Lesné, SE, Liao, D, Araque, A & Lee, MK 2019, 'Tau is required for progressive synaptic and memory deficits in a transgenic mouse model of ?-synucleinopathy', Acta Neuropathologica, vol. 138, no. 4, pp. 551-574. https://doi.org/10.1007/s00401-019-02032-w
Khan, SS, LaCroix, M, Boyle, G, Sherman, MA, Brown, JL, Amar, F, Aldaco, J, Lee, MK, Bloom, GS & Lesné, SE 2018, 'Bidirectional modulation of Alzheimer phenotype by alpha-synuclein in mice and primary neurons' Acta Neuropathologica, vol. 136, no. 4, pp. 589-605. https://doi.org/10.1007/s00401-018-1886-z
Chiang, ACA, Fowler, SW, Reddy, R, Pletnikova, O, Troncoso, JC, Sherman, MA, Lesné, SE & Jankowsky, JL 2018, 'Discrete Pools of Oligomeric Amyloid-? Track with Spatial Learning Deficits in a Mouse Model of Alzheimer Amyloidosis' American Journal of Pathology, vol. 188, no. 3, pp. 739-756. https://doi.org/10.1016/j.ajpath.2017.11.011
Larson, ME, Greimel, SJ, Amar, F, LaCroix, M, Boyle, G, Sherman, MA, Schley, H, Miel, C, Schneider, JA, Kayed, R, Benfenati, F, Lee, MK, Bennett, DA & Lesné, SE 2017, 'Selective lowering of synapsins induced by oligomeric ?-synuclein exacerbates memory deficits' Proceedings of the National Academy of Sciences of the United States of America, vol. 114, no. 23, pp. E4648-E4657. https://doi.org/10.1073/pnas.1704698114
Amar, F, Sherman, MA, Rush, T, Larson, M, Boyle, G, Chang, L, Götz, J, Buisson, A & Lesné, SE 2017, 'The amyloid-? oligomer A??56 induces specific alterations in neuronal signaling that lead to tau phosphorylation and aggregation' Science Signaling, vol. 10, no. 478, aal2021. https://doi.org/10.1126/scisignal.aal2021
Sherman, MA, LaCroix, M, Amar, F, Larson, ME, Forster, C, Aguzzi, A, Bennett, DA, Ramsden, M & Lesné, SE 2016, 'Soluble conformers of A? and tau alter selective proteins governing axonal transport' Journal of Neuroscience, vol. 36, no. 37, pp. 9647-9658. https://doi.org/10.1523/JNEUROSCI.1899-16.2016
Alfonso, SI, Callender, JA, Hooli, B, Antal, CE, Mullin, K, Sherman, MA, Lesné, SE, Leitges, M, Newton, AC, Tanzi, RE & Malinow, R 2016, 'Gain-of-function mutations in protein kinase C? (PKC?) may promote synaptic defects in Alzheimer's disease' Science Signaling, vol. 9, no. 427, ra47. https://doi.org/10.1126/scisignal.aaf6209
Lesné, SE 2014, 'Toxic oligomer species of amyloid-? in Alzheimer's disease, a timing issue' Swiss Medical Weekly, vol. 144, 14021. https://doi.org/10.4414/smw.2014.14021
Fowler, SW, Chiang, ACA, Savjani, RR, Larson, ME, Sherman, MA, Schuler, DR, Cirrito, JR, Lesné, SE & Jankowsky, JL 2014, 'Genetic modulation of soluble A? rescues cognitive and synaptic impairment in a mouse model of Alzheimer's disease' Journal of Neuroscience, vol. 34, no. 23, pp. 7871-7885. https://doi.org/10.1523/JNEUROSCI.0572-14.2014
Lesné, SE 2013, 'Breaking the code of amyloid-? oligomers' International Journal of Cell Biology. https://doi.org/10.1155/2013/950783