Varshney, M. | Search bioRxiv

bioRxiv2024

ERβ mediates sex-specific protection in the App-NL-G-F mouse model of Alzheimer's disease

Menopausal loss of neuroprotective estrogen is thought to contribute to the sex differences in Alzheimers disease (AD). Activation of estrogen receptor beta (ER{beta}) can be clinically relevant since it avoids the negative systemic effects of ER activation. However, very few studies have explored ER{beta}-mediated neuroprotection in AD, and no information on its contribution to the sex differences in AD exists. In the present study we specifically explored the role of ER{beta} in mediating sex-specific protection against AD pathology in the clinically relevant AppNL-G-F knock-in mouse model of amyloidosis, and if surgical menopause (ovariectomy) modulates pathology in this model. We treated male and female AppNL-G-F mice with the selective ER{beta} agonist LY500307 and subset of the females was ovariectomized prior to treatment. Memory performance was assessed and a battery of biochemical assays were used to evaluate amyloid pathology and neuroinflammation. Primary microglial cultures from male and female wild-type and ER{beta}-knockout mice were used to assess ER{beta}s effect on microglial activation and phagocytosis. We find that ER{beta} activation protects against amyloid pathology and cognitive decline in male and female AppNL-G-F mice. Ovariectomy increased soluble amyloid beta (A{beta}) in cortex and insoluble A{beta} in hippocampus, but had otherwise limited effects on pathology. We further identify that ER{beta} does not alter APP processing, but rather exerts its protection through amyloid scavenging that at least in part is mediated via microglia in a sex-specific manner. Combined, we provide new understanding to the sex differences in AD by demonstrating that ER{beta} protects against AD pathology differently in males and females, warranting reassessment of ER{beta} in combating AD.

neuroscience↗

bioRxiv2024

Olive phenolic compounds, potent tankyrase 1 inhibitor exhibit anti colon cancer effects by blocking Wnt/β-catenin pathway

Colon cancer (CC) needs special attention to develop novel targets and therapeutic approaches, as the total number of morbidity and mortality is growing rapidly. Although Olive has been long reported for its anti-CC activities but the mode is not completely understood yet. Here, we targeted tankysare 1 (TNKS), an important mediator of the Wnt/{beta}-catenin pathway, crucial in colon carcinogenesis. Bioinformatics analysis revealed that the mutation and copy number alterations of TNKS is found to be 12% whereas the proteins expression of TNKS is moderate to high in tumor groups vs normal in CC datasets. On the more, TNKS and its positively associated genes are found to be concomitant with several carcinogenesis related biological processes and signaling pathways. Further, three olive phytochemicals (apigenin, luteolin, and quercetin), which were shortlisted by employing filters like drug likeness and toxicity screening, molecular docking and finally molecular dynamics simulations, can target tankyrase 1. These ployphenols demonstrated cytotoxic effect in CC (HT-29) cells either alone or in combination. Further, these compounds successfully reduced {beta}-catenin level and its target genes (CCND1, CDK4, and MYC). Overall, inhibition of the Wnt/{beta}-catenin pathway by targeting tankyrase 1 was revealed as one of the anti-CC mechanisms of olive polyphenols.

cancer biology↗