Activation of α7nAch receptors ameliorates α-synuclein pathology in the brain and gut of a subacute MPTP mouse model of Parkinson's disease

Abstract

Parkinson's disease (PD) is a neurological disorder that causes a gradual decrease in mobility. Abnormal α-synuclein (α-syn) levels and aggregation contribute to PD development. The dissemination of α-synuclein pathology via the gut-brain axis has emerged as a critical aspect in α-synucleinopathies, including PD. Recently, α7 nicotinic acetylcholine receptor (α7nAchR) agonists have been proposed as promising agents for treating PD, owing to their biological properties such as anti-inflammatory effects. This study aims to investigate whether activation of α7nAchR improves α-synuclein pathology in the brain and gut of a mouse model of PD. We found that α7nAchR agonists, GTS-21 and PNU-282987, induced behavioral recovery and improved nigrostriatal dopaminergic neurotransmission in a subacute MPTP mouse model of PD. In addition, GTS-21 and PNU-282987 facilitated α-syn clearance in the brain and distal colon, as evidenced by a considerable reduction in the accumulation of pathogenic forms of α-syn. Accordingly, GTS-21 and PNU-282987 were found to promote the AMPK-mTOR autophagy signaling pathway. Furthermore, GTS-21 and PNU-282987 exerted anti-inflammatory effects, reducing the levels of proinflammatory mediators such as inducible nitric oxide synthase, interleukin-6, and tumor necrosis factor-α in both the brain and gut. To validate the specific effects of α7nAchR agonists, subacute MPTP mice were pretreated with methyllycaconitine (MLA), a selective α7nAchR antagonist before GTS-21 administration. Pretreatment with MLA abolished the GTS-21-elicited behavioral recovery, α-syn clearance, and anti-inflammatory effects in the brain and gut. Therefore, α7nAchR activation may be a potential candidate strategy for the treatment of PD by altering α-syn aggregation in the brain and gut. © 2025 The Authors