SRC-1 Knockout Exerts No Effect on Amyloid β Deposition in APP/PS1 Mice

Sex hormones act throughout the entire brain of both males and females via both genomic and nongenomic receptors. Sex hormones can act through many cellular and molecular processes that alter structure and function of neural systems and influence behavior as well as providing neuroprotection. Within neurons, sex hormone receptors are found in nuclei and are also located near membranes, where they are associated with presynaptic terminals, mitochondria, spine apparatus, and postsynaptic densities. Sex hormone receptors also are found in glial cells. Hormonal regulation of a variety of signaling pathways as well as direct and indirect effects on gene expression induce spine synapses, up- or downregulate and alter the distribution of neurotransmitter receptors, and regulate neuropeptide expression and cholinergic and GABAergic activity as well as calcium sequestration and oxidative stress. Many neural and behavioral functions are affected, including mood, cognitive function, blood pressure regulation, motor coordination, pain, and opioid sensitivity. Subtle sex differences exist for many of these functions that are developmentally programmed by hormones and by not yet precisely defined genetic factors, including the mitochondrial genome. These sex differences and responses to sex hormones in brain regions, which influence functions not previously regarded as subject to such differences, indicate that we are entering a new era of our ability to understand and appreciate the diversity of gender-related behaviors and brain functions. © 2016 Wiley Periodicals, Inc.

Synaptic dysfunction and abnormal processing of amyloid precursor protein (APP) are early pathological features in Alzheimer’s disease (AD). Recently, non-coding RNAs such as microRNAs (miRNAs) and circular RNAs (circRNAs) have been reported to contribute to the pathogenesis of AD. We found an age-dependent elevation of miR-138 in APP/PS1 (presenilin-1) mice. MiR-138 inhibited the expression of ADAM10 [a disintegrin and metalloproteinase domain-containing protein 10], promoted amyloid beta (Aβ) production, and induced synaptic and learning/memory deficits in APP/PS1 mice, while its suppression alleviated the AD-like phenotype in these mice. Overexpression of sirtuin 1 (Sirt1), a target of miR-138, ameliorated the miR-138-induced inhibition of ADAM10 and elevation of Aβ in vitro . The circRNA HDAC9 (circHDAC9) was predicted to contain a miR-138 binding site in several databases. Its expression was inversely correlated with miR-138 in both Aβ-oligomer-treated N2a cells and APP/PS1 mice, and it co-localized with miR-138 in the cytoplasm of N2a cells. CircHDAC9 acted as a miR-138 sponge, decreasing miR-138 expression, and reversing the Sirt1 suppression and excessive Aβ production induced by miR-138 in vitro . Moreover, circHDAC9 was decreased in the serum of both AD patients and individuals with mild cognitive impairment. These results suggest that the circHDAC9/miR-138/Sirt1 pathway mediates synaptic function and APP processing in AD, providing a potential therapeutic target for its treatment.

By integrating growth pathways on which cancer cells rely, steroid receptor coactivators (SRC-1, SRC-2, and SRC-3) represent emerging targets in cancer therapeutics. High-throughput screening for SRC small molecule inhibitors (SMIs) uncovered MCB-613 as a potent SRC small molecule "stimulator" (SMS). We demonstrate that MCB-613 can super-stimulate SRCs' transcriptional activity. Further investigation revealed that MCB-613 increases SRCs' interactions with other coactivators and markedly induces ER stress coupled to the generation of reactive oxygen species (ROS). Because cancer cells overexpress SRCs and rely on them for growth, we show that we can exploit MCB-613 to selectively induce excessive stress in cancer cells. This suggests that over-stimulating the SRC oncogenic program can be an effective strategy to kill cancer cells.