The α-synucleinopathies constitute a subset of neurodegenerative disorders, of which Parkinson’s disease (PD) is the most common worldwide, characterized by the accumulation of misfolded α-synuclein in the cytoplasm of neurons, which spreads in a prion-like manner to anatomically interconnected brain areas. However, it is not clear how α-synucleinopathy triggers neurodegeneration. We recently developed a rat model through a single intranigral administration of the neurotoxic β-sitosterol β-D-glucoside (BSSG), which produces α-synucleinopathy. In this model, we aimed to evaluate the temporal pattern of levels in oxidative and nitrosative stress and mitochondrial complex I (CI) dysfunction and how these biochemical parameters are associated with neurodegeneration in different brain areas with α-synucleinopathy (Substantia nigra pars compacta, the striatum, in the hippocampus and the olfactory bulb, where α-syn aggregation spreads). Interestingly, an increase in oxidative stress and mitochondrial CI dysfunction accompanied neurodegeneration in those brain regions. Furthermore, in silico analysis suggests a high-affinity binding site for BSSG with peroxisome proliferator-activated receptors (PPAR) alpha (PPAR-α) and gamma (PPAR-γ). These findings will contribute to elucidating the pathophysiological mechanisms associated with α-synucleinopathies and lead to the identification of new early biomarkers and therapeutic targets.

The aryl hydrocarbon receptor (AhR) is a transcription factor that acts as a nuclear receptor mediating xenobiotic metabolism and environmental responses. Recent evidence suggests that the AhR is implicated in maintaining homeostasis or triggering pathological effects by modulating different physiological responses in the nervous system. However, the underlying mechanisms of the AhR-induced effects in the hippocampus remain unclear. Herein, we report a previously unknown role for the AhR in the pathogenesis of a transient global ischemic insult. Comparative analysis of the expression of HIF-1α, nNOS, iNOS, IL6, KAT II, and claudin 5 in the hippocampus of AhR ^+/+ and AhR ^-/- mice after bilateral common carotid artery occlusion revealed differential modulation. We report that AhR ^-/- mice significantly reduced the blood-brain barrier (BBB) dysfunction and neuronal death in hippocampus-CA1 caused by the ischemic insult, inducing neuroprotection. In addition, blocking the AhR with Resveratrol (a competitive antagonist) decreased neuronal degeneration and preserved the integrity of the BBB in the hippocampus associated with a neuroprotective effect. In summary, we showed that the AhR is an essential regulator for maintaining the BBB in the hippocampus and responds to inflammatory conditions and oxidative stress; further pharmacological targeting of AhR signaling may reduce the pathologic changes caused by an ischemic insult in the hippocampus.

Huntington’s disease (HD) is a hereditary neurodegenerative disorder of the central nervous system that mainly affects the basal ganglia and has no cure. The mutation is located at an abnormal expansion of the CAG triplet in the Huntingtin gene. Humans show psychiatric, behavioural and motor disorders. Transgenic animal models are essential to the study of HD since the disease only affects humans. Therefore, the aim of this article was to describe the formation and maintenance of and to validate the progressive neurological phenotype of an R6/1 transgenic mouse colony. To achieve our objective, the colony founder was imported from Jackson Laboratories, and the mice were kept under controlled environmental conditions. The animals were bred at the vivarium of the Instituto Nacional de Neurología y Neurocirugía Man­uel Velasco Suárez. The R6/1 transgenic mice were successfully bred and showed genetic and phenotypic characteristics similar to the ones previously reported. Our colony is currently established and validated with the condi­tions of our vivarium and has produced more than four generations of R6/1 mice. The establishment of the R6/1 colony and its maintenance through generation is an advantage since it allows us to follow the authenticity of the transgenic mice regarding their phenotypic and motor behaviours. Fur­thermore, these animals can be compared with other transgenic mice that reproduce some of the main characteristics of the disease manifested in hu­mans, making these transgenic R6/1 mice a useful tool for the study of HD.

In this study, we evaluate lipids and select proteins in human lung fibroblasts (hLFs) to interrogate changes occurring due to aging and senescence. To study single cell populations, a comparison of cells adhered onto slides using poly-D-lysine versus centrifugal force deposition was first analyzed to determine whether specific alterations were observed between preparations. The poly-D-lysine approach was than utilized to interrogate the lipidome of the cell populations and further evaluate potential applications of the MALDI-immunohistochemistry (IHC) platform for single-cell level analyses. Two protein markers of senescence, vimentin and p21, were both observed within the fibroblast populations and quantified. Lipidomic analysis of the fibroblasts found twelve lipids significantly altered because of replicative senescence, including fatty acids, such as stearic acid, and ceramide phosphoethanolamine species (CerPE). Similar to previous reports, alterations were detected in putative fatty acid building blocks, ceramides, among other lipid species. Altogether, our results reveal the ability to detect lipids implicated in senescence and show alterations to protein expression between normal and senescent fibroblast populations, including differences between young and aged cells. This report is the first time that the MALDI-IHC system has been utilized at a single-cell level to analyze both protein expression and lipid profiles in cultured cells, with a particular focus on changes associated with aging and senescence.