Alzheimer\'s disease (AD) is characterized by the accumulation of abnormally folded amyloid β-protein (Aβ) in the brain parenchyma and phosphorylated tau in neurons. Presenilin (PS, PSEN) 1 and PS2 are essential components of γ-secretase, which is responsible for the cleavage of amyloid precursor protein (APP) to generate Aβ. PSEN mutations are associated with tau aggregation in frontotemporal dementia, regardless of the presence or absence of Aβ pathology. However, the mechanism by which PS regulates tau aggregation is still unknown. Here, we found that tau phosphorylation and secretion were significantly increased in PS double-knock-out (PS1/2-/-) fibroblasts compared with wild-type fibroblasts. Tau-positive vesicles in the cytoplasm were significantly increased in PS1/2-/- fibroblasts. Active GSK-3β was increased in PS1/2-/- fibroblasts, and inhibiting GSK3β activity in PS1/2-/- fibroblasts resulted in decreased tau phosphorylation and secretion. Transfection of WT human PS1 and PS2 reduced the secretion of phosphorylated tau and active GSK-3β in PS1/2-/- fibroblasts. However, PS1D257A without γ-secretase activity did not decrease the secretion of phosphorylated tau. Furthermore, nicastrin deficiency also increased tau phosphorylation and secretion. These results suggest that deficient PS complex maturation may increase tau phosphorylation and secretion. Thus, our studies discover a new pathway by which PS regulates tau phosphorylation/secretion and pathology independent of Aβ and suggest that PS serves as a potential therapeutic target for treating neurodegenerative diseases involving tau aggregation.

Despite the therapeutic advances in treating malignancies, the efficient radiotherapeutic approaches with deprived adverse reactions still represent a potential clinical inquiry. The current study aims to elucidate the role of gallic acid (GA) in modifying the hazardous renal cytotoxicity induced by acute exposure to radiation. The MTT test was used to evaluate the viability of Vero cells exposed to 2 Gy gamma radiation with or without incubation of GA. In an in vivo model, male Wistar rats were divided into four experimental groups (n = 6): Control, Irradiated (IRR, 5 Gy), GA (100 mg/kg, i.p.) + IRR, and Glycogen synthase kinase inhibitor (GSKI, 3 mg/kg, i.p.) + IRR. Based on the MTT toxicity assay, from 0 and up to 5 μM dosages of GA did not demonstrate any cytotoxicity to Vero cells. The optimal GA dose that could protect the cells from radiation was 5 μM. Furthermore, GA exerted a protective effect from gamma radiation on renal tissue as indicated by corrected renal functions, decreased LDH level in serum, and balanced oxidative status, which is indicated by decreased tissue contents of NOx and TBARS with a significant increase of reduced GSH. These outcomes were inferred by the upregulation of nuclear factor erythroid 2-related factor 2 (Nrf2) expression. The overall molecular impact of radiation in damaging the renal tissue may be explained by modifying the upstream AKT activity and its downstream targets GSK-3β/Notch-1. Here, we concluded that the anticipated adverse reaction in the course of radiation exposure could be protected by daily administration of GA.

Apigenin, a natural flavonoid compound found in chamomile (Matricaia chamomilla L.) from the Asteraceae family, has been shown in our previous study to possess antimyocardial hypertrophy and anti-cardiac fibrosis effects. However, its effects and mechanisms on the pyroptosis of cardiomyocytes induced by doxorubicin (DOX) are poorly understood. The objective of this study was to investigate the role of GSK-3β and the effects of apigenin in DOX-induced cardiotoxicity. H9c2 cells stimulated with DOX were treated with SB216763 and apigenin. Additionally, a mouse model of DOX-induced cardiotoxicity was prepared and further treated with apigenin and SB216763 for 30 days. The findings revealed that treatment with SB216763 or apigenin resulted in a significant reduction in the levels of pyroptosis-related factors. Furthermore, the phosphorylation of GSK-3β was enhanced while the phosphorylation of nuclear factor-kB (NF-κB) p65 was reduced following treatment with either SB216763 or apigenin. Conversely, the effects of apigenin treatment were nullified in siRNA-GSK-3β-transfected cells. Results from computer simulation and molecular docking analysis supported that apigenin could directly target the regulation of GSK-3β. Therefore, our study confirmed that the inhibition of GSK-3β and treatment with apigenin effectively suppressed the pyroptosis of cardiomyocytes in both DOX-stimulated H9c2 cells and mice. These benefits may be attributed in part to the decrease in GSK-3β expression and subsequent reduction in NF-κB p65 activation. Overall, our findings revealed that the pharmacological targeting of GSK-3β may offer a promising therapeutic approach for alleviating DOX-induced cardiotoxicity.

BACKGROUND: Alzheimer\'s disease (AD) is the most prevalent dementia, affecting a large number of populations. Despite being under scrutiny for decades, an effective therapeutic option is still not available.
RESULTS: This study explores the therapeutic role of a nootropic herb Bacopa monnieri (BM) in AD-like pathological conditions produced by injecting preformed amyloid-β42 (Aβ42) fibril bilaterally into hippocampus of Wistar rats, and ethanolic extract of BM is orally administered for 4 weeks. Assessment of behavioral changes reveals that BM treatment ameliorates Aβ42-induced cognitive impairment and compromised explorative behavior. Supplementation of BM also reduces oxidative stress biomarkers, proinflammatory cytokines, and cholinesterase activity in the AD rats. Additionally, BM treatment restores Bcl-2-associated X protein (Bax)/ B-cell lymphoma 2 (Bcl-2) imbalance, increases neurotrophic factors expression, and prevents neurodegeneration validated by quantifying Nissl-positive hippocampal neurons. Interestingly, BM administration eliminates amyloid plaques in the hippocampal region and normalizes the Aβ42-induced increase in phospho-tau and total tau expression. Mechanistic investigations reveal that BM interacts with glycogen synthase kinase (GSK-3β) and restores Wnt/β-catenin signaling.
CONCLUSIONS: BM has been used in diet as a nootropic herb for several centuries. This study highlights the anti-Alzheimer activity of BM from the behavioral to the molecular level by modulating mitochondrial dysfunction, and GSK-3β mediates the Wnt/β-catenin signaling pathway.

The failures in Alzheimer\'s disease (AD) therapy strongly suggest the importance of reconsidering the research strategies analyzing other mechanisms that may take place in AD as well as, in general, in other neurodegenerative dementias. Taking into account that in AD a variety of defects result in neurotransmitter activity and signaling efficiency imbalance, neuronal cell degeneration and defects in damage/repair systems, aberrant and abortive cell cycle, glial dysfunction, and neuroinflammation, a target may be represented by the intracellular signaling machinery provided by the kinome. In particular, based on the observations of a relationship between cancer and AD, we focused on cancer kinases for targeting neurodegeneration, highlighting the importance of targeting the intracellular pathways at the intersection between cell metabolism control/duplication, the inhibition of which may stop a progression in neurodegeneration.

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.