Association between body mass index and glymphatic function using diffusion tensor image-along the perivascular space (DTI-ALPS) in patients with Parkinson's disease.

Background: Obesity is considered a risk factor for the development of several neurodegenerative diseases, including Parkinson's disease (PD). Recent studies have revealed that glymphatic function is compromised in PD patients. This study aims to investigate the impact of different body mass index (BMI) statuses on glymphatic system function in PD patients using the diffusion tensor image analysis along the perivascular space (DTI-ALPS) method. Methods: This study used a cross-sectional study design. A total of 145 PD patients were retrospectively enrolled in Parkinson's Progression Markers Initiative (PPMI) from 2010-2013. Eligibility criteria included diagnosis of PD based on PPMI criteria. Diffusion tensor image (DTI) scans (diffusion gradient =64, b-value =1,000 s/mm2, slice thickness =2 mm) were acquired, and the analysis along the perivascular space (ALPS) index of each subject was calculated. The patient cohort was categorized into three groups based on BMI: normal weight (N=49), overweight (N=69), and obese (N=27). The difference in ALPS index among groups was performed by one-way analysis of variance (ANOVA). Partial correlation analysis was used to observe the relationship between ALPS index, BMI status, and demographics. Spearman's rank correlation coefficient and multivariable linear regression analyses were used to identify factors associated with ALPS index. Results: PD patients with higher BMI exhibited a reduced ALPS index (normal weight > overweight > obese), and the ALPS index for patients with obesity was statistically significantly lower than that for patients with normal weight (P<0.001). After adjusting for age, sex, years of education, handedness, and disease duration, a significant negative correlation between the ALPS index and BMI was observed in the PD patients (R=-0.275, P<0.001). Furthermore, a negative correlation between the ALPS index and the severity of motor symptoms was identified in the subgroup of overweight (R=-0.318, P=0.01), rather than in the normal weight and obese groups. Conclusions: High BMI has a negative impact on the glymphatic function in PD patients, suggesting that weight control may have clinical relevance in the management of PD patients.

Activation of Wnt/ß-catenin signaling restores insulin sensitivity in insulin resistant neurons through transcriptional regulation of IRS-1.

Aberrant expression and phosphorylation of insulin receptor substrate 1 (IRS-1) contribute to brain insulin resistance. However, the underlying mechanism remains elusive. The insulin signaling and Wnt/ß-catenin signaling are two critical pathways for normal cellular function, which interact in both peripheral tissues and the brain and may contribute to insulin resistance. In this study, we aimed to investigate the regulation of IRS-1 and its downstream insulin signaling by Wnt/ß-catenin signaling in primary neurons. We found that the Wnt agonist Wnt3a enhances the insulin signaling in neurons at the basal state via up-regulation of IRS-1. Moreover, Wnt3a up-regulates IRS-1 expression and effectively ameliorates insulin resistance in rat primary neurons induced by chronic high insulin exposure. The insulin-mediated glucose uptake is also stimulated by Wnt3a at both basal and insulin resistant states. We observed that Wnt activation up-regulates IRS-1 gene transcription and the subsequent protein expression in SH-SY5Y cells and rat primary neurons via different means of Wnt/ß-catenin signaling activation, including S33Y ß-catenin over-expression, CHIR99021 and Wnt3a treatment. We further clarified the molecular mechanism of IRS-1 transcriptional activation by Wnt/ß-catenin signaling. The Wnt transcription factor TCF4 binds to the -529 bp to -516 bp of the human IRS-1 promoter fragment and activates IRS-1 transcription. Overall, these data suggested that Wnt/ß-catenin signaling positively regulates IRS-1 and insulin signaling and protects against insulin resistance in neurons.

Dual-specificity tyrosine phosphorylation-regulated kinase 1A ameliorates insulin resistance in neurons by up-regulating IRS-1 expression.

Insulin resistance in the brain is a pathological mechanism that is shared between Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM). Although aberrant expression and phosphorylation of insulin receptor substrate 1 (IRS-1) contribute to insulin resistance, the underlying mechanism remains elusive. In this study, we used several approaches, including adeno-associated virus-based protein overexpression, immunoblotting, immunoprecipitation, immunohistochemistry, and in situ proximal ligation assays, to investigate the function of dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) in IRS-1 regulation and the downstream insulin signaling in neurons. We found that DYRK1A overexpression up-regulated IRS-1 expression by slowing turnover of the IRS-1 protein. We further observed that DYRK1A directly interacted with IRS-1 and phosphorylated IRS-1's multiple serine residues. Of note, DYRK1A and IRS-1 were coordinately up-regulated in the prefrontal cortex of db/db mice brain. Furthermore, DYRK1A overexpression ameliorated chronic high insulin-induced insulin resistance in SH-SY5Y cells as well as in primary rat neurons. These findings suggest that DYRK1A protects against insulin resistance in the brain by elevating IRS-1 expression.