Pramipexole improves cognitive deficits and synaptic plasticity impairments in 3xTg-AD mice through enhancing autophagy

Autophagy dysfunction plays important roles in the pathogenesis of Alzheimer's disease (AD), and activation of Autophagy might be a potential strategy in AD treatment. Although some Autophagy inducers play beneficial roles in AD, no Autophagy Inducer has been available in AD clinical treatment due to lack of efficacy or obvious side effects. A recent study demonstrated that pramipexole (PPX) can activate Autophagy in the brain without interfering with protein synthesis, thereby avoiding the side effects associated with prolonged use of an Autophagy Inducer. However, whether PPX can exert neuroprotective effects on AD and whether its potential mechanism is related to Autophagy remains unclear. In the present study, the effects of PPX on the cognitive function of 3xTg-AD mice were observed using multiple behavioral tests, then synaptic plasticity was evaluated through in vivo hippocampal electrophysiological recordings and by measuring synaptic proteins, while Aβ and tau pathologies were detected using immunofluorescence staining and western blot. Finally, Autophagy was detected and the potential target was predicted using bioinformatics analysis, qRT-PCR and molecular docking. Results demonstrated that PPX significantly improved cognitive deficits and hippocampal long-term potentiation (LTP) depression, increased the expression of PSD95, reduced Aβ deposition and tau hyperphosphorylation, activated Autophagy by increasing LC3-II/LC3-I ratios and decreasing p62 levels, and restored Beclin1 expression. Bioinformatics analysis identified MAPK1 as a key target in PPX-ameliorated AD by enhancing Autophagy. These findings suggest that PPX alleviates AD-related cognitive deficits and neuropathologies through increased Autophagy, emphasising its potential as a disease-modifying therapeutic strategy for AD.

Alzheimer's disease; Autophagy; Cognitive function; Pramipexole.