Leucettine L41 Ameliorates Tau pathology and neuroinflammation in Parkinson's disease models

Aberrant protein phosphorylation and sustained neuroinflammatory activation are key biochemical features of experimental parkinsonism. Dysregulated tau processing and excessive microglial reactivity have been implicated in motor dysfunction associated with dopaminergic injury. In the present study, we evaluated the biochemical and functional effects of Leucettine L41 using biochemical, cellular, and in vivo systems.

In an in vitro tau aggregation assay, L41 reduced the ThT fluorescence, indicating the suppression of fibril formation. In SH-SY5Y neuronal cells, L41 decreased tau phosphorylation at the Ser202/Thr205 site. In lipopolysaccharide-stimulated BV-2 microglial cells, L41 suppressed the production of nitric oxide, TNF-α, IL-1β, and IL-6, demonstrating its anti-inflammatory activity. Notably, L41 did not prevent toxin-induced neuronal cytotoxicity, suggesting that its primary action may not involve direct neuroprotection. In an MPTP-induced mouse model of Parkinson's disease, systemic L41 administration improved motor performance, accompanied by reduced tau phosphorylation and attenuated microglial activation in brain tissue.

These findings indicate that L41 modulates tau aggregation, phosphorylation, and neuroinflammatory signaling in experimental parkinsonism, in association with functional motor improvement.