HSP70 is one of the main molecular chaperones involved in the cellular stress response. Besides its chaperone action, HSP70 also modulates the immune response. Increased susceptibility to toxic insults in intra- and extracellular environments has been associated with insufficient amounts of inducible HSP70 in adult neurons. On the other hand, exogenous HSP70 administration has demonstrated neuroprotective effects in experimental models of age-related disorders. In this regard, this study investigated the effects of exogenous HSP70 in an animal model of dopaminergic denervation of the nigrostriatal axis. After unilateral intrastriatal injection with 6-hydroxydopamine (6-OHDA), the animals received purified recombinant HSP70 through intranasal administration (2 μg/rat/day) for 15 days. Our results indicate a neuroprotective effect of intranasal HSP70 against dopaminergic denervation induced by 6-OHDA. Exogenous HSP70 improved motor impairment and reduced the loss of dopaminergic neurons caused by 6-OHDA. Moreover, HSP70 modulated neuroinflammatory response in the substantia nigra , an important event in Parkinson’s disease pathogenesis. Specifically, HSP70 treatment reduced microglial activation and astrogliosis induced by 6-OHDA, as well as IL-1β mRNA expression in this region. Also, recombinant HSP70 increased the protein content of HSP70 in the substantia nigra of rats that received 6-OHDA. These data suggest the neuroprotection of HSP70 against dopaminergic neurons damage after cellular stress. Finally, our results indicate that HSP70 neuroprotective action against 6-OHDA toxicity is related to inflammatory response modulation.

Oligomerization and aggregation of misfolded forms of α-synuclein are believed to be key molecular mechanisms in Parkinson’s disease (PD) and other synucleinopathies, so extensive research has attempted to understand these processes. Among diverse post-translational modifications that impact α-synuclein aggregation, glycation may take place at several lysine sites and modify α-synuclein oligomerization, toxicity, and clearance. The receptor for advanced glycation end products (RAGE) is considered a key regulator of chronic neuroinflammation through microglial activation in response to advanced glycation end-products, such as carboxy-ethyl-lysine, or carboxy-methyl-lysine. The presence of RAGE in the midbrain of PD patients has been reported in the last decades and this receptor was proposed to have a role in sustaining PD neuroinflammation. However, different PD animal models demonstrated that RAGE is preferentially expressed in neurons and astrocytes, while recent evidence demonstrated that fibrillar, non-glycated α-synuclein binds to RAGE. Here, we summarize the available data on α-synuclein glycation and RAGE in the context of PD, and discuss about the questions yet to be answered that may increase our understanding of the molecular bases of PD and synucleinopathies.

Background: Targeting the nuclear RXR receptors has been associated with brainspecific roles with striking therapeutic potential for Alzheimer's Disease (AD), with similar observations to its dimerization partners such as LXR and PPAR whose responses are also under influence of RXR activation. Treatment with bexarotene, a selective RXR agonist, leads to significant recovery of cognitive loss in variable mice AD-like models -and also activates neurodevelopment and plasticity pathways in adult mice brains. Our hypothesis is that neural stem cells (NSC) residing in the adult brain directly respond to bexarotene, leading to improved neurogenesis and other effects compatible with brain recovery. Method:We employed an in vitro strategy using NSCs isolated from the subventricular zone of adult rats' brains. Adult NCSs were treated with bexarotene from neurosphere proliferative stage to differentiated states, and the cell-fate consequences were evaluated through morphometric analysis and immunofluorescence of cell markers. Result:In proliferative stages, bexarotene-treated adult NSCs exhibited increased cell outgrowth from neurospheres. Bexarotene treatment also led to changes in the cell fate of differentiating cells, with a marked increase in GFAP staining after differentiation. Relatively to newborn neurons, we found a decrease in DCX positive staining of neuroblasts after bexarotene treatment. However, Tuj1 staining of neurons was preserved. Neurite number, length, and bifurcations in differentiated neurons were unaffected by bexarotene. Conclusion:Adult NSCs respond to bexarotene by increasing migration abilities and generating more GFAP+ cells. Results indicate that RXR activation by bexarotene in adult NSCs preserves, but does not activate, neuronal differentiation and neurite complexity. The significance of the increased GFAP+ glial cell population, as well as the decreased DCX+ young neurons, remains to be unrevealed. Finally, we did not observe clear bexarotene-induced changes in neurosphere proliferation, but the effect of RXR activation over pluripotency in these cells needs further investigation. These findings address a gap in our knowledge regarding the brain effects of bexarotene, substantiating the search and possible application of RXR-based approaches to AD.