The Crocus sativus Compounds trans-Crocin 4 and trans-Crocetin Modulate the Amyloidogenic Pathway and Tau Misprocessing in Alzheimer Disease Neuronal Cell Culture Models.

Crocus sativus L. natural compounds have been extensively used in traditional medicine for thousands of years. Recent research evidence is now emerging in support of its therapeutic potential for different pathologies including neurodegenerative diseases. Herein, the C. sativus L. natural compounds trans-crocin 4 and trans-crocetin were selected for in depth molecular characterization of their potentially protective effects against Alzheimer's Disease (AD), utilizing two AD neuronal cell culture models (SH-SY5Y overexpressing APP and PC12 expressing hyperphosphorylated tau). Biologically relevant concentrations, ranging from 0.1 µM to 1 mM, applied for 24 h or 72 h, were well tolerated by differentiated wild type SH-SY5Y and PC12 cells. When tested on neuronally differentiated SH-SY5Y-APP both trans-crocin 4 and trans-crocetin had significant effects against amyloidogenic pathways. Trans-crocin 4 significantly decreased of ß-secretase, a key enzyme of the amyloidogenic pathway, and APP-C99, while it decreased γ-secretases that generate toxic beta-amyloid peptides. Similarly, trans-crocetin treatment led to a reduction in ß- and γ-secretases, as well as to accumulation of cellular AßPP. When tested on the neuronally differentiated PC12-htau cells, both compounds proved effective in suppressing the active forms of GSK3ß and ERK1/2 kinases, as well as significantly reducing total tau and tau phosphorylation. Collectively, our data demonstrate a potent effect of trans-crocin 4 and trans-crocetin in suppressing key molecular pathways of AD pathogenesis, rendering them a promising tool in the prevention and potentially the treatment of AD.

Beneficial Effects of Sideritis scardica and Cichorium spinosum against Amyloidogenic Pathway and Tau Misprocessing in Alzheimer's Disease Neuronal Cell Culture Models.

BACKGROUND: Natural products are a significantly underutilized source of potential treatments against human disease. Alzheimer's disease (AD) is a prime example of conditions that could be amenable to such treatments as suggested by recent findings. OBJECTIVE: Aiming to identify novel potentially therapeutic approaches against AD, we assessed the effects of Cichorium spinosum and Sideritis scardica extracts, both distinct components of the Mediterranean diet. METHODS/RESULTS: After the detailed characterization of the extracts' composition using LC-HRMS methods, they were evaluated on two AD neuronal cell culture models, namely the AßPP overexpressing SH-SY5Y-AßPP and the hyperphosphorylated tau expressing PC12-htau. Initially their effect on cell viability of SH-SY5Y and PC12 cells was examined, and subsequently their downstream effects on AßPP and tau processing pathways were investigated in the SH-SY5Y-AßPP and PC12-htau cells. We found that the S. scardica and C. spinosum extracts have similar effects on tau, as they both significantly decrease total tau, the activation of the GSK3ß, ERK1 and/or ERK2 kinases of tau, as well as tau hyperphosphorylation. Furthermore, both extracts appear to promote AßPP processing through the alpha, non-amyloidogenic pathway, albeit through partly different mechanisms. CONCLUSIONS: These findings suggest that C. spinosum and S. scardica could have a notable potential in the prevention and/or treatment of AD, and merit further investigations at the in vivo level.

The impact of the hormonal milieu and stress-associated hypothalamic dopaminergic activation on the rapid compensatory adrenal growth in cycling female rats.

OBJECTIVE: We sought to investigate the impact of emotional and surgical stress applied in two hormonally different estrous-cycle phases as well as the hypothalamic dopaminergic involvement on the rapid compensatory adrenal growth (CAG) and the individual adrenal growth (IAG) in rats. DESIGN: After surgery for left and sham adrenalectomy (Adx) carried out on either diestrus-2 (DE-2) or proestrus (PE), CAG and IAG were evaluated in PE or estrus (E), respectively. Hypothalamic dopaminergic activity was also assessed by measuring dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) levels in DE-2, PE and E in controls and in PE and E in sham and left adrenalectomized rats. All groups experienced similar chronic emotional stress assessed by the emotional reactivity score recorded during vaginal screening. RESULTS: In controls, DOPAC levels in DE-2 were higher than in PE and E. In PE, following surgery in DE-2, DOPAC levels and DOPAC/DA ratio were increased compared to PE controls; CAG was not significant, while negative correlations of IAG and CAG with DOPAC/DA ratio were observed. In E, CAG and IAG were significant, while dopaminergic activity was not increased compared to E controls. CONCLUSIONS: The significant CAG and IAG following left Adx in PE but not in DE-2 suggest a pronounced positive impact of the hormonal milieu on this process. The profound attenuation of CAG and IAG in PE suggests a negative effect of stress-associated dopaminergic activation.