Alpha-synuclein oligomers impair memory through glial cell activation and via Toll-like receptor 2

Pietro La Vitola, Claudia Balducci, Milica Cerovic, Giulia Santamaria, Edoardo Brandi, Federica Grandi, Laura Caldinelli, Laura Colombo, Maria Grazia Morgese, Luigia Trabace, Loredano Pollegioni, Diego Albani, Gianluigi Forloni

Research output: Contribution to journalArticle

Abstract

Alpha-synuclein oligomers (α-synOs) are emerging as crucial factors in the pathogenesis of synucleinopathies. Although the connection between neuroinflammation and α-syn still remains elusive, increasing evidence suggests that extracellular moieties activate glial cells leading to neuronal damage. Using an acute mouse model, we explored whether α-synOs induce memory impairment in association to neuroinflammation, addressing Toll-like receptors 2 and 4 (TLR2 and TLR4) involvement. We found that α-synOs abolished mouse memory establishment in association to hippocampal glial activation. On brain slices α-synOs inhibited long-term potentiation. Indomethacin and Ibuprofen prevented the α-synOs-mediated detrimental actions. Furthermore, while the TLR2 functional inhibitor antibody prevented the memory deficit, oligomers induced memory deficits in the TLR4 knockout mice. In conclusion, solely α-synOs induce memory impairment likely inhibiting synaptic plasticity. α-synOs lead to hippocampal gliosis that is involved in memory impairment. Moreover, while the oligomer-mediated detrimental actions are TLR2 dependent, the involvement of TLR4 was ruled out.

Original languageEnglish
Pages (from-to)591-602
Number of pages12
JournalBrain, Behavior, and Immunity
Volume69
DOIs
Publication statusPublished - Mar 2018

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    La Vitola, P., Balducci, C., Cerovic, M., Santamaria, G., Brandi, E., Grandi, F., Caldinelli, L., Colombo, L., Morgese, M. G., Trabace, L., Pollegioni, L., Albani, D., & Forloni, G. (2018). Alpha-synuclein oligomers impair memory through glial cell activation and via Toll-like receptor 2. Brain, Behavior, and Immunity, 69, 591-602. https://doi.org/10.1016/j.bbi.2018.02.012