Therapeutic development in Alzheimer’s Disease (AD) has for the most part been focused on reducing β-amyloid load. Nevertheless, neurofibrillary tangles (NFTs), produced by aggregation of hyper-phosphorylated Tau protein, correlate with neurodegeneration and cognitive impairment significantly better than amyloid accumulation in AD patients. Here we report that P301S mice, a model of Tau-mediated neurodegeneration, carrying mutant variants of the p75 neurotrophin receptor (p75 NTR ) deficient in RhoA/ROCK signaling are protected from neurodegeneration and cognitive impairment. Both p75 ∆DD , lacking the death domain, and triple mutant p75 KKEA , unable to interact with RhoGDI, decreased insoluble Tau species, reduced gliosis, neurodegeneration and synapse loss, and improved spatial learning and memory in P301S mice. Intriguingly, p75 C259A , a variant unresponsive to neurotrophins but still competent for RhoA signaling induced by myelin-derived ligands, did not afford any neuroprotection. P301S neurons expressing p75 ∆DD or p75 KKEA , but not p75 C259A , showed reduced phospho-Tau and ROCK and GSK3β activity, the two main kinases responsible for Tau phosphorylation. In line with this, treatment with myelin-associated glycoprotein (MAG) enhanced Tau phosphorylation and ROCK activity in P301S neurons expressing wild type p75 NTR or p75 C259A , but not p75 ∆DD or p75 KKEA . Together, these results indicate that p75 NTR contributes to AD Tauopathy by enhancing the activity of the RhoA-ROCK pathway.
JiaJia Wang,YanJun Li,Ke Lai,QiMei Zhong,Konstantin A. Demin,Allan V. Kalueff,Cai Song
Neuroinflammation and metabolic deficits contribute to the etiology of human affective disorders, such as anxiety and depression. The zebrafish ( Danio rerio ) has recently emerged as a powerful new model organism in CNS disease modeling. Here, we exposed zebrafish to 2% glucose and 10% cholesterol for 19 days to experimentally induce type 2 diabetes (DM) and to assess stress responses, microglia , inflammation and apoptosis . We analyzed zebrafish anxiety-like behavior in the novel tank and light-dark box (Days 15–16) tests, as well as examined their biochemical and genomic biomarkers (Day 19). Confirming DM-like state in zebrafish, we found higher whole-body glucose, triglyceride , total cholesterol, low-density lipoprotein levels and glucagon mRNA expression, and lower high-density lipoprotein levels. DM zebrafish also showed anxiety-like behavior, elevated whole-body cortisol and cytokines IFN-γ and IL-4, as well as higher brain mRNA expression of the glucocorticoid receptor , CD11b (a microglial biomarker), pro-inflammatory cytokines IL-6 and TNF-α (but not IL-1β or anti-inflammatory cytokines IL-4 and IL-10), GFAP (an astrocytal biomarker), neurotrophin BDNF , its receptors p75 and TrkB, as well as apoptotic Bax and Caspase-3 (but not BCl-2 ) genes. Collectively, this supports the overlapping nature of DM-related affective pathogenesis and emphasizes the role of peripheral and central inflammation and apoptosis in DM-related affective and neuroendocrine deficits in zebrafish.
危险品化学品经营许可证（带存储）