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Behavioral changes or neuropsychiatric symptoms (NPSs) are common features in dementia and are associated with accelerated cognitive impairment and earlier deaths. However, how NPSs are intertwined with cognitive decline remains elusive. In this study, we identify that the basolateral amygdala (BLA) is a key brain region that is associated with mood disorders and memory decline in the AD course. During the process from pre‐ to post‐onset in AD, the dysfunction of parvalbumin (PV) interneurons and pyramidal neurons in the amygdala leads to hyperactivity of pyramidal neurons in the basal state and insensitivity to external stimuli. We further demonstrate that serotonin (5‐HT) receptors in distinct neurons synergistically regulate the BLA microcircuit of AD rather than 5‐HT levels, in which both restrained inhibitory inputs by excessive 5‐HT1AR signaling in PV interneurons and depolarized pyramidal neurons via upregulated 5‐HT2AR contribute to aberrant neuronal hyperactivity. Downregulation of these two 5‐HT receptors simultaneously enables neurons to resist β‐amyloid peptides (Aβ) neurotoxicity and ameliorates the mood and cognitive defects. Therefore, our study reveals a crucial role of 5‐HT receptors for regulating neuronal homeostasis in AD pathogenesis, and this would provide early intervention and potential targets for AD cognitive decline. [ABSTRACT FROM AUTHOR]

Deguelin, a natural component derived from leguminous plants, has been used as pesticide in some regions. Accumulating evidence show that deguelin has promising chemopreventive and therapeutic activities against cancer cells. This study shows that low concentrations of deguelin can lead to significant delay in zebrafish embryonic development through growth inhibition and induction of apoptosis. Furthermore, we identified fibroblast growth factor receptor 4 ( FGFR4) as the putative target of deguelin. The candidate was initially identified by a microarray approach and then validated through in vitro experiments using hormone-responsive ( MCF-7) and nonresponsive ( MDA- MB-231) human breast cancer cell lines. The results show that deguelin suppressed cell proliferation and induced apoptosis in both cancer cell lines, but not in Hs 578Bst cells, by blocking PI3K/ AKT and mitogen-activated protein kinases ( MAPK) signaling. The FGFR4 mRNA and protein level also diminished in a dose-dependent manner. Interestingly, we found that forced FGFR4 overexpression attenuated deguelin-induced proliferative suppression and apoptotic cell death in both zebrafish and MCF-7 cell lines, p- AKT and p- ERK levels were restored upon FGFR4 overexpression. Taken together, our results strongly suggest that deguelin inhibition of PI3K/ AKT and MAPK signaling in zebrafish and breast cancer cell lines is partially mediated through down-regulation of FGFR4 activity. [ABSTRACT FROM AUTHOR]