Background: Parkinson's disease (PD) is a neurodegenerative disorder orphan of valuable therapies. PD is neuropathological characterized by intracellular Lewy bodies formed by aggregated α-synuclein (α-syn ) in mesencephalic region and neuroinflammation significantly contribute to the pathogenesis of the disease. In the complex scenario of PD single target therapy cannot be beneficial, a therapeutic strategy simultaneously affecting α-syn aggregation and neuroinflammation may be useful to affect PD progression. Recently, the antimicrobial drug Doxycycline (Doxy) has been demonstrated to inhibit α-syn aggregation. In addition, we have reported that Doxy at subantibiotic doses efficiently counteracts memory impairment and neuroinflammation in a transgenic (Tg) mouse model of Alzheimer's Disease. Based on the multiple action mechanism of Doxy, we herein investigate the potential therapeutic properties of Doxy in a Tg PD mouse model. Method: A53T mice and their non-Tg (NTG) litter mates were intraperitoneally treated with 10mg/Kg Doxy for 30 days. At the end of treatment, cognitive and motor performances were evaluated in the Novel object recognition test (NORT), Nesting test, Beam-walk and Paw grip endurance. In addition, hippocampal long term potentiation (LTP) was assessed. Neuropathological markers were explored through immunohistological and biochemical approaches.Result: Doxy abolished the cognitive deficit in the NORT. Moreover, Doxy restored daily life activity of A53T mice in the Nesting test, which is dependent by hippocampal and cortical networks. Aside from an effect at cognitive level, we found that Doxy treatment ameliorated motor performances in both the Beam-walk test and in the Paw grip endurance. The effect on cognitive functions was strictly linked to a reduced neuronal loss in the cortex and hippocampus of A53T+Doxy compared to A53T+Veh group. Moreover, glial activation were blocked by our pharmacological approach both in the cortex and hippocampus. In addition, Doxy treatment restored hippocampal LTP in association with the dampening of pro-inflammatory cytokines expression. Conclusion:Doxy emerges as a valuable therapeutic approach to counteract both symptoms and neuropathological hallmarks in the complex scenario of a Tg PD mouse model. Moreover, our results depict PD as a novel field for repurposing Doxy and corroborate previous data indicating Doxy as a multi-target drug.

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