Sleep deprivation-induced TLR4/MyD88/NF-κB pathway dysregulation worsens cognitive impairment in Parkinson's Disease.

Abstract

Parkinson's disease (PD) is a common neurodegenerative disorder. It has motor symptoms and non motor symptoms, like cognitive impairment, sleep disturbance. Studies show PD patient with sleep disorders show more severe cognitive impairment. To investigate the underlying mechanisms, we used a PD zebrafish model induced by 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and simulated insomnia by sleep deprivation (SD). Behavioral tests showed that SD exacerbated cognitive impairment. SD aggravated vascular loss and dopaminergic neuron damage. RT-qPCR analysis revealed the highest expression levels of Toll Like Receptor 4 (tlr-4), Myeloid Differentiation Primary Response 88 (myd88), Nuclear Factor Kappa B (nfκb), Caspase 3 (casp3), BCL2 Associated X, Apoptosis Regulator (bax) in the SD co-treatment group, indicating maximal Toll Like Receptor 4 (TLR4)/Myeloid Differentiation Primary Response 88 (MyD88)/Nuclear Factor Kappa B (NF-κB) pathway activation and apoptosis levels, while Autophagy Related 5 (atg5) expression was lowest, indicating severe autophagy dysfunction. ELISA detected the highest levels of IL-6 and TNF-α, indicating maximal neuroinflammation. This study clarified the mechanism of SD exacerbating PD cognitive impairment: SD upregulates the TLR4/MyD88/NF-κB pathway, which intensifies neuroinflammation and apoptosis and led to autophagy dysfunction. This study revealed the potential mechanism between sleep disturbance and cognitive impairment in PD patients, provided a theoretical basis for the therapies targeting the TLR4/MyD88/NF-κB pathway, holds significant clinical significance for enhancing the quality of life of PD patients.