Autophagy Inhibition and Inflammation Activation Induced by Phosphorylated Alpha-synuclein Through Toll-like Receptor 2 Pathway in the Hippocampus of MPTP Mouse Model of Parkinson’s Disease Contribute to Its Cognitive Function Decline in the Early Stage

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Abstract Background: To evaluate consecutively the cognitive function of a chronic mouse model of Parkinson’s disease (PD) induced by 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine/probenecid (MPTP/p) in different modeling periods, and to study the characteristics of cognitive decline in PD and its molecular mechanism. Methods: In this study, we used MPTP and probenecid to induce a chronic PD mouse model, the Y-maze test to evaluate the cognitive function of the model in different modeling periods, western blotting (WB) to quantify phosphorylated alpha-synuclein (p-α-syn), Toll-like receptors (TLRs), Nod-like receptors (NLRs), Choline acetyltransferase (ChAT), glial fibrillary acidic protein (GFAP), p62, Interleukin-1β (IL-1β) and other related indicators, immunohistochemical staining (IHC) to characterize the expression of p-α-syn, immunofluorescence staining (IF) to observe the co-localization of p-α-syn and cholinergic neurons (ChAT+) or astroglias (GFAP+) in the hippocampus. The TLR2 inhibitor CU-CPT22 was used to intervene in the subacute MPTP PD mouse model and then the expression of TLR2, ChAT, GFAP, p62 and IL-1β were evaluated again. Results: In the Y-maze test after 1/2/3/4/5 weeks of administration, the percentage of bouts to the Novel arm and the percentage of duration in the Novel arm of the MPTP/p group mice were lower than those of the Saline group mice, and there were statistical differences at the second week. At the same time, the p-α-syn monomer in the hippocampus of chronic MPTP/p PD mice increased, accompanied by the increase of GFAP, TLR2, Nuclear factor-κB (NF-κB), NLR pyrin domain containing 3 (NLRP3), p62 and IL-1β, and the decrease of the ratio of LC3Ⅱ to LC3I (LC3Ⅱ/I). The p-α-syn in the hippocampus increased, and co-localized significantly with GFAP and slightly with ChAT. TLR2 inhibitor CU-CPT22 can reduce the expression of GFAP, p62 and IL-1β in the subacute MPTP mouse model. Conclusion: Autophagy inhibition and inflammation activation induced by p-α-syn through TLR2 pathway in the hippocampus of MPTP mouse model of Parkinson’s disease contribute to its cognitive function decline in the early stage, indicating the potential of TLR2 as a therapeutic target for PD cognitive decline.

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