Environmental Health Perspectives is an Open Access journal published by the National Institute of Environmental Health Sciences. Environmental Health Perspectives is an Open Access journal published by the National Institute of Environmental Health Sciences.

FTIR spectroscopy was used to characterize and compare the temperature‐ and pressure‐induced unfolding of ribonuclease A and a set of its variants engineered in a hydrophobic region of the C‐terminal part of the molecule postulated as a CFIS. The results show for all the ribonucleases investigated, a cooperative, two‐state, reversible unfolding transition using both pressure and temperature. The relative stabilities, among the different sites and different variants at the same site, monitored either through the changes in the position of the maximum of the amide I′ band and the tyrosine band, or the maximum of the band assigned to the β‐sheet structure, corroborate the results of a previous study using fourth‐derivative UV absorbance spectroscopy. In addition, variants at position 108 are the most critical for ribonuclease structure and stability. The V108G variant seems to present a greater conformational flexibility than the other variants. The pressure‐ and temperature‐denaturated states of all the ribonucleases characterized retained some secondary structure. However, their spectral maxima were centered at different wavenumbers, which suggests that pressure‐ and temperature‐denaturated states do not have the same structural characteristics. Nevertheless, there was close correlation between the pressure and temperature midpoint transition values for the whole series of protein variants, which indicated a common tendency of stability toward pressure and heat.

Dysregulation of the hypothalamic‐pituitary‐adrenal (HPA) axis occurs early in Alzheimer's disease (AD), associated with elevated circulating glucocorticoids (GC) and glucocorticoid receptors (GR) signaling impairment. However, the precise role of GR in the pathophysiology of AD remains unclear. Using an acute model of AD induced by the intracerebroventricular injection of amyloid‐β oligomers (oAβ), we analyzed cellular and behavioral hallmarks of AD, GR signaling pathways, processing of amyloid precursor protein, and enzymes involved in Tau phosphorylation. We focused on the prefrontal cortex (PFC), particularly rich in GR, early altered in AD and involved in HPA axis control and cognitive functions. We found that oAβ impaired cognitive and emotional behaviors, increased plasma GC levels, synaptic deficits, apoptosis and neuroinflammatory processes. Moreover, oAβ potentiated the amyloidogenic pathway and enzymes involved both in Tau hyperphosphorylation and GR activation. Treatment with a selective GR modulator (sGRm) normalized plasma GC levels and all behavioral and biochemical parameters analyzed. GR seems to occupy a central position in the pathophysiology of AD. Deregulation of the HPA axis and a feed‐forward effect on PFC GR sensitivity could participate in the etiology of AD, in perturbing Aβ and Tau homeostasis. These results also reinforce the therapeutic potential of sGRm in AD.