Neuroinflammation and Alpha-Synuclein Oligomer Toxicity in the Pathogenesis of Lewy Body Dementia and Parkinson's Disease

Aggregated α-synuclein has emerged as the core constituent of the typical neuronal inclusions found in Parkinson’s disease and Lewy body dementia. Therefore, huge efforts have been made to unveil the mechanisms underlying α-syn toxicity. Accumulating evidence suggests extracellular α-synuclein oligomers (α-synOs) as potential culprits involved in the neurodegenerative process. To elucidate the pathways mediating α-synO non-cell- autonomous actions, several mechanisms including uncontrolled neuroinflammatory responses and protein-protein interactions have been put forward. Through an acute model based on the intracerebroventricular (ICV) injection of α-synuclein monomers, oligomers or fibrils in C57BL/6N mice we demonstrate that only α-synOs impair memory establishment in association with glial activation. Furthermore, our findings identify neuroinflammation as a driving force of α-synO detrimental action on memory, and the involvement of the Toll-like receptor 2. Based on recent data depicting the cellular prion protein (PrPC) as an α-synO interactor, we have further investigated its role in fostering α- synO harmful activities. We found that PrPC does not mediate α-synO toxicity in vitro or α- synO-induced memory deficiency in vivo. In fact, PrPC knock-out mice ICV injected with α-synOs display both memory impairment and gliosis. Consistently, our in vitro biochemical studies do not reveal any direct PrPC-α-synO binding. To evaluate the influence of neuroinflammation on PD pathogenesis, we have developed a “double-hit” approach. Using an acute mouse model based on the peripheral administration of lipopolysaccharide (LPS) and subsequent ICV injection of α-synOs at an inactive dose, we demonstrate that the LPS induces a long-lasting neuroinflammatory response enhancing α-synO actions. Moreover, we show that the LPS peripheral administration worsens cognitive deficits even in an A53T PD mouse model. Altogether, by identifying neuroinflammation as an α-synO-mediator and as a factor influencing the initiation/progressions of PD, we highlight it as a valuable research topic to identify potential targets for developing new therapeutic strategies

P2‐111: MESENCHYMAL STEM CELL‐DERIVED SECRETOME FULLY REPLICATE CELL‐MEDIATED NEURO‐REPARATIVE ACTIVITIES IN THE APP/PS1 MOUSE MODEL OF ALZHEIMER'S DISEASE

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Toll-like receptor 4-dependent glial cell activation mediates the impairment in memory establishment induced by \u3b2-amyloid oligomers in an acute mouse model of Alzheimer's disease

Amyloid-β oligomers (AβO) are species mainly involved in the synaptic and cognitive dysfunction in Alzheimer's disease. Although their action has been described mainly at neuronal level, it is now clear that glial cells govern synaptic activity in their resting state, contributing to new learning and memory establishment. In contrast, when activated, they may lead to synaptic and cognitive dysfunction. Using a reliable acute AβO-mediated mouse model of AD, we explored whether the memory alteration AβOs induce relies on the activation of glial cells, and if Toll-like receptor 4 (TLR4), pivotal in the initiation of an immune response, is involved

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

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