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)... Show moreDysregulation 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-beta oligomers (oA beta), 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 oA beta impaired cognitive and emotional behaviors, increased plasma GC levels, synaptic deficits, apoptosis and neuroinflammatory processes. Moreover, oA beta 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 A beta and Tau homeostasis. These results also reinforce the therapeutic potential of sGRm in AD. Show less
The PID-directed shift in PIN polarity has been broadly accepted as one of the essential mechanisms for the regulation of auxin transport polarity. We verified that both PID functionality and its... Show moreThe PID-directed shift in PIN polarity has been broadly accepted as one of the essential mechanisms for the regulation of auxin transport polarity. We verified that both PID functionality and its subcellular localization do not depend on PDK1 function. However, by detailed analysis on these phenotypes and the expression of the auxin response reporter, we found the pdk1 pdk2 double mutant to be impaired in auxin transport in vascular tissues. Together with other mutant phenotypes, we suspect that PDK1 may be the master regulator of AGC1 kinases. The pdk1 pdk2 short root phenotype caused by phloem differentiation defects phenocopied the pax mutant. Complementation results of wild type and phosphomimic PAX in the pdk1 pdk2 background suggest that PDK1-dependent PAX phosphorylation and activation are essential for its full biological function. We also explain the molecular basis of PDK1 basal localization and the unnecessity of this polarity for vascular development. In addition, we investigated downstream action after PID phosphorylation. Several conserved tyrosine residues close to serine phosphorylation sites in the PIN1 and PIN2 HLs are mutated. Two of these tyrosines redundantly affected PIN polarity. However, PID mediated phosphorylation and tyrosine-based PIN trafficking are independent processes. Show less
