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

Alpha-synuclein oligomers (alpha-synOs) are emerging as crucial factors in the pathogenesis of synucleinopathies. Although the connection between neuroinflammation and alpha-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 alpha-synOs induce memory impairment in association to neuroinflammation, addressing Toll-like receptors 2 and 4 (TLR2 and TLR4) involvement. We found that alpha-synOs abolished mouse memory establishment in association to hippocampal glial activation. On brain slices alpha-synOs inhibited long-term potentiation. Indomethacin and Ibuprofen prevented the alpha-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 alpha-synOs induce memory impairment likely inhibiting synaptic plasticity. alpha-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. (C) 2018 Elsevier Inc. All rights reserved.