Recent evidence indicates that testosterone is neuroprotective, however, the underlying mechanism(s) remains to be elucidated. In this study, we investigated the hypothesis that androgens induce mitogen-activated protein kinase (MAPK) signaling in neurons, which subsequently drives neuroprotection. We observed that testosterone and its non-aromatizable metabolite dihydrotestosterone (DHT) rapidly and transiently activate MAPK in cultured hippocampal neurons, as evidenced by phosphorylation of extracellular signal-regulated kinase (ERK)-1 and ERK-2. Importantly, pharmacological suppression of MAPK/ERK signaling blocked androgenmediated neuroprotection against b-amyloid toxicity. Androgen activation of MAPK/ERK and neuroprotection also was observed in PC12 cells stably transfected with androgen receptor (AR), but in neither wild-type nor empty vectortransfected PC12 cells. Downstream of ERK phosphorylation, we observed that DHT sequentially increases p90 kDa ribosomal S6 kinase (Rsk) phosphorylation and phosphorylationdependent inactivation of Bcl-2-associated death protein (Bad). Prevention of androgen-induced phosphorylation of Rsk and Bad blocked androgen neuroprotection. These findings demonstrate AR-dependent androgen activation of MAPK/ERK signaling in neurons, and specifically identify a neuroprotective pathway involving downstream activation of Rsk and inactivation of Bad. Elucidation of androgen-mediated neural signaling cascades will provide important insights into the mechanisms of androgen action in brain, and may present a framework for therapeutic intervention of age-related neurodegenerative disorders.
-Amyloid protein (A) has been implicated as a key molecule in the neurodegenerative cascades of Alzheimer's disease (AD). A directly induces neuronal apoptosis, suggesting an important role of A neurotoxicity in AD neurodegeneration. However, the mechanism(s) of A-induced neuronal apoptosis remain incompletely defined. In this study, we report that A-induced neuronal death is preceded by selective alterations in expression of the Bcl-2 family of apoptosis-related genes. Specifically, we observe that A significantly reduces expression of antiapoptotic Bcl-w and Bcl-x L , mildly affects expression of bim, Bcl-2, and bax, but does not alter expression of bak, bad, bik, bid, or BNIP3. A-induced downregulation of Bcl-w appears to contribute to the mechanism of apoptosis, because A-induced neuronal death was significantly increased by Bcl-w suppression but significantly reduced by Bcl-w overexpression. Downstream of Bcl-w, A-induced neuronal apoptosis is characterized by mitochondrial release of second mitochondrion-derived activator of caspase (Smac), an important precursor event to cell death. We observed that Smac release was potentiated by suppression of Bcl-w and reduced by overexpression of Bcl-w. Next, we investigated the upstream mediator of A-induced Bcl-w downregulation and Smac release. We observed that A rapidly activates c-Jun N-terminal kinase (JNK). Pharmacological inhibition of JNK effectively inhibited all measures of A apoptosis: Bcl-w downregulation, Smac release, and neuronal death. Together, these results suggest that the mechanism of A-induced neuronal apoptosis sequentially involves JNK activation, Bcl-w downregulation, and release of mitochondrial Smac, followed by cell death. Complete elucidation of the mechanism of A-induced apoptosis promises to accelerate development of neuroprotective interventions for the treatment of AD.
The synergistic effect of chemotherapy and ablation using high-intensity focused ultrasound (HIFU) is realized with a newly developed drug-delivery system. The system comprises an ultrathin silica shell surrounding a poly(lactic-co-glycolic acid) nanoemulsion core containing the drug (CPT) and a perfluorocarbon (PFOB). This nanosystem presents many advantages in drug delivery, such as excellent structural stability, high drug-loading capacity, and rapid HIFU-mediated drug release.
Estrogen is neuroprotective against a variety of insults, including -amyloid peptide (A); however, the underlying mechanism(s) is not fully understood. Here, we report that 17-estradiol (E2) selectively regulates neuronal expression of the Bcl-2 family (bcl-2, bcl-x, bcl-w, bax, bak, bad, bik, bnip3, bid, and bim).
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