Myeloid-specific blockade of notch signaling alleviates dopaminergic neurodegeneration in Parkinson's disease by dominantly regulating resident microglia activation through NF-κB signaling.

Yolk sac-derived microglia and peripheral monocyte-derived macrophages play a key role during Parkinson's disease (PD) progression. However, the regulatory mechanism of microglia/macrophage activation and function in PD pathogenesis remains unclear. Recombination signal-binding protein Jκ (RBP-J)-mediated Notch signaling regulates macrophage development and activation. In this study, with an 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) hydrochloride-induced acute murine PD model, we found that Notch signaling was activated in amoeboid microglia accompanied by a decrease in tyrosine hydroxylase (TH)-positive neurons. Furthermore, using myeloid-specific RBP-J knockout (RBP-JcKO) mice combined with a PD model, our results showed that myeloid-specific disruption of RBP-J alleviated dopaminergic neurodegeneration and improved locomotor activity. Fluorescence-activated cell sorting (FACS) analysis showed that the number of infiltrated inflammatory macrophages and activated major histocompatibility complex (MHC) II+ microglia decreased in RBP-JcKO mice compared with control mice. Moreover, to block monocyte recruitment by using chemokine (C-C motif) receptor 2 (CCR2) knockout mice, the effect of RBP-J deficiency on dopaminergic neurodegeneration was not affected, indicating that Notch signaling might regulate neuroinflammation independent of CCR2+ monocyte infiltration. Notably, when microglia were depleted with the PLX5622 formulated diet, we found that myeloid-specific RBP-J knockout resulted in more TH+ neurons and fewer activated microglia. Ex vitro experiments demonstrated that RBP-J deficiency in microglia might reduce inflammatory factor secretion, TH+ neuron apoptosis, and p65 nuclear translocation. Collectively, our study first revealed that RBP-J-mediated Notch signaling might participate in PD progression by mainly regulating microglia activation through nuclear factor kappa-B (NF-κB) signaling.

[Influence of road on breeding habitat of Nipponia nippon based on MaxEnt model]. / 基于MaxEnt模型的道路对朱鹮繁殖地的影响.

Quantitative study on effects of roads on suitable breeding habitats of wildlife is one of topics that need in-depth research in road ecology. Crested ibis (Nipponia nippon), a first class nationally protected bird species, is the species of interest in this research. Using the Maximum Entropy Models (MaxEnt) in the Species Distribution Model (SDM) toolbox of ArcGIS, autocorrelation of environmental variables were analyzed and environmental variables with r>0.8 were removed. Ten environmental variables were chosen as impact factors for the breeding habitat of crested ibis, including mean temperature of coldest quarter, landscape type, normalized difference vegetation index(NDVI), slope, aspect, distance to waters, distance to paddy field, distance to high-grade roads (expressway, national way, provincial way), and distance to low-grade roads (country road). By analyzing the contribution rate of each environmental variable, the results showed that the mean temperature of coldest quarter, landscape type, distance to paddy field, and distance to high-grade roads were the main factors determining breeding habitat of crested ibis. The suitable distribution of crested ibis' nesting area was under the following scenarios: variable road present (scenario1), high-grade road absent (scenario2), and low-grade road absent (scenario 3). The results showed that the presence of roads affected suitable nesting areas of crested ibis with high-grade roads showing a larger influence than low-grade roads. The presence of high-grade roads and low-grade roads decreased the suitable nesting areas of crested ibis by 66.23 and 35.69 km2, respectively. The crested ibis preferred to nest in areas distant from high-grade roads, with an average road avoidance distance of 1500 m. This study was of great significance for formulating management measures to protect crested ibis and provide a reference for quantitative assessment on impacts of engineering and construction projects on wildlife.