Despite evidence for a pathogenic role of amyloid plaques and associated neuronal dystrophy, it has become apparent in the past decade that soluble, non-fibrillar amyloid-beta (Aβ) assemblies, also called Aβ oligomers, may represent the bioactive molecules involved in the physiopathology 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. The Lesné laboratory is examining whether and how Aβ oligomers can interact at neuronal plasma membranes with specific receptors involved in the cellular form of memory by combining biochemical and functional assays.
Our group also focuses on examining whether soluble Aβ oligomers represent the missing link between tau and amyloid pathologies in Alzheimer's disease. To this end, we use novel bigenic mice expressing the full human tau gene and APP, the precursor protein of Aβ. We investigate the effect of short- and long-term exposures of soluble Aβ oligomers on tau biology by integrating in vitro and in vivo approaches.
Lastly, the Lesné laboratory recently reported that soluble form(s) of alpha-synuclein (αSyn), usually linked to Parkinson’s disease, could play a central role in modulating the physiopathology of Alzheimer’s disease. New transgenic mouse models are under way to further validate the potential impact of αSyn in Alzheimer’s disease.
(For a comprehensive list of recent publications, refer to PubMed, a service provided by the National Library of Medicine.)
- Lesné S SNCA genetic lowering reveals differential cognitive function of alpha-synuclein dependent on sex. Acta Neuropathol Commun. in press, 2022.
- Nguyen PH, Ramamoorthy A, Sahoo BR, Zheng J, Faller P, Straub JE, Dominguez L, Shea JE, Dokholyan NV, De Simone A, Ma B, Nussinov R, Najafi S, Ngo ST, Loquet A, Chiricotto M, Ganguly P, McCarty J, Li MS, Hall C, Wang Y, Miller Y, Melchionna S, Habenstein B, Timr S, Chen J, Hnath B, Strodel B, Kayed R, Lesné S, Wei G, Sterpone F, Doig AJ, Derreumaux P. Amyloid Oligomers: A joint experimental/computational perspective on Alzheimer's disease, Parkinson's disease, type II diabetes, and amyotrophic lateral sclerosis. Chem Rev. 2021 Feb 24;121(4):2545-2647.
- Kayed R, Dettmer U, Lesné SE. Soluble endogenous oligomeric α-synuclein species in neurodegenerative diseases: Expression, spreading, and cross-talk. J Parkinsons Dis. 2020;10(3):791-818.
- 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. Tau is required for progressive synaptic and memory deficits in a transgenic mouse model of α-synucleinopathy. Acta Neuropathol. 2019;138(4):551-574.
- Khan SS, LaCroix M, Boyle G, Sherman MA, Brown JL, Amar F, Aldaco J, Lee MK, Bloom GS, Lesné SE. Bidirectional modulation of Alzheimer phenotype by alpha-synuclein in mice and primary neurons. Acta Neuropathol. 2018;136(4):589-605.
- Chiang ACA, Fowler SW, Reddy R, Pletnikova O, Troncoso JC, Sherman MA, Lesné SE, Jankowsky JL. Discrete pools of oligomeric amyloid-β track with spatial learning deficits in a mouse model of Alzheimer amyloidosis. Am J Pathol. 2018;188(3):739-756.
- 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. Selective lowering of synapsins induced by oligomeric α-synuclein exacerbates memory deficits. Proc Natl Acad Sci USA. 2017;114:E4648-E4657.
- Amar F, Sherman MA, Rush T, Larson M, Boyle G, Chang L, Götz J, Buisson A, Lesné SE. The amyloid-β oligomer Aβ*56 induces specific alterations in neuronal signaling that lead to tau phosphorylation and aggregation. Sci Signal. 2017 May 9;10(478) pii: eaal2021.
- Sherman MA, LaCroix M, Amar F, Larson ME, Forster C, Aguzzi A, Bennett DA, Ramsden M, Lesné SE. Soluble conformers of Aβ and tau alter selective proteins governing axonal transport. J Neurosci. 2016;36:9647-9658.
- Alfonso SI, Callender JA, Hooli B, Antal CE, Mullin K, Sherman MA, Lesné SE, Leitges M, Newton AC, Tanzi RE, Malinow R. Gain-of-function mutations in protein kinase Cα (PKCα) may promote synaptic defects in Alzheimer's disease. Sci Signal. 2016 May 10;9(427):ra47.
- Lesné SE. Toxic oligomer species of amyloid-β in Alzheimer's disease, a timing issue. Swiss Med Wkly. 2014 Nov 6;144:w14021.
- Fowler SW, Chiang AC, Savjani RR, Larson ME, Sherman MA, Schuler DR, Cirrito JR, Lesné SE, Jankowsky JL. Genetic modulation of soluble Aβ rescues cognitive and synaptic impairment in a mouse model of Alzheimer's disease. J Neurosci. 2014;34:7871-85.
- Lesné SE, Sherman MA, Grant M, Kuskowski M, Schneider JA, Bennett DA, Ashe KH. Brain amyloid-β oligomers in ageing and Alzheimer's disease. Brain. 2013;136(Pt 5):1383-98.
- Lesné SE. Breaking the code of amyloid-β oligomers. Int J Cell Biol. 2013;2013:950783.
- Larson M, Sherman MA, Amar F, Nuvolone M, Schneider JA, Bennett DA, Aguzzi A, Lesné SE. The complex PrP(c)-Fyn couples human oligomeric Aβ with pathological tau changes in Alzheimer's disease. J Neurosci. 2012;32:16857-16871a.
- Larson ME, Sherman MA, Greimel S, Kuskowski M, Schneider JA, Bennett DA, Lesné SE. Soluble α-Synuclein Is a Novel Modulator of Alzheimer's Disease Pathophysiology. J Neurosci. 2012;32:10253-10266.
- Larson ME, Lesné SE. Soluble Aβ oligomer production and toxicity. J Neurochem. 2012;120 Suppl 1:125-139.
Current Graduate Students:
Jennifer Brown (Neuroscience, University of Minnesota)
Ross Pelzel (Neuroscience, University of Minnesota)
Nick Rozema (Neuroscience, University of Minnesota)
Former Graduate Students:
Fatou Amar (Ph.D. 2015, Neuroscience, University of Minnesota).
Susan Greimel (Ph.D. 2014, Neuroscience, University of Minnesota).