EARLY NEUROINFLAMMATION DRIVES COGNITIVE AND SYNAPTIC IMPAIRMENTS IN Α-SYNUCLEIN PARKINSON’S DISEASE: THERAPEUTIC RESCUE BY IL-1Β BLOCKADE

Parkinson’s disease (PD), a pathological condition characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta and the accumulation of misfolded alpha-synuclein (α-syn), is also linked to neuroinflammation and cognitive impairments related to mesocorticolimbic dopaminergic dysfunction.
In our experimental animal PD model, three months after unilateral striatal injection of human α-syn pre-formed fibrils (PFFs), male and female mice showed significant deficits in cognitive and social tasks. Extracellular field potential recordings revealed a complete loss of long-term potentiation in the hippocampal CA1 neurons in both sexes. Immunofluorescence analysis of the CA1 region, distinguishing the stratum radiatum and the pyramidal layer, revealed increased microglial activation, with high levels of NLRP3⁺ and CD68⁺ cells in PFF-injected mice. Moreover, levels of IL-18 and IL-1β were higher in the hippocampus of parkinsonian mice compared with the control groups, indicating an enhanced inflammatory response in this brain region. Despite advances in diagnostics, therapies targeting α-syn have not yet provided clinical benefits, emphasizing the important but poorly understood role of early glial activation and neuroinflammation in PD development. To address this, mice were treated with Anakinra, an interleukin-1β receptor antagonist. Remarkably, PFF-injected mice treated with Anakinra showed significant improvements in behavior, synaptic plasticity, and neuroinflammatory regulation, highlighting the potential of Anakinra as promising treatment in experimental PD.
These findings provide new insights into the role of neuroinflammation in PD-related cognitive and social deficits and suggest that targeting IL-1β signaling could be an effective strategy to slow disease progression.