Pharmacological doses of melatonin impede cognitive decline in tau-related Alzheimer models, once tauopathy is initiated, by restoring the autophagic flux.

Alterations in autophagy are increasingly being recognized in the pathogenesis of proteinopathies like Alzheimer's disease (AD). This study was conducted to evaluate whether melatonin treatment could provide beneficial effects in an Alzheimer model related to tauopathy by improving the autophagic flux and, thereby, prevent cognitive decline. The injection of AAV-hTauP301L viral vectors and treatment/injection with okadaic acid were used to achieve mouse and human ex vivo, and in vivo tau-related models. Melatonin (10 µmol/L) impeded oxidative stress, tau hyperphosphorylation, and cell death by restoring autophagy flux in the ex vivo models. In the in vivo studies, intracerebroventricular injection of AAV-hTauP301L increased oxidative stress, neuroinflammation, and tau hyperphosphorylation in the hippocampus 7 days after the injection, without inducing cognitive impairment; however, when animals were maintained for 28 days, cognitive decline was apparent. Interestingly, late melatonin treatment (10 mg/kg), starting once the alterations mentioned above were established (from day 7 to day 28), reduced oxidative stress, neuroinflammation, tau hyperphosphorylation, and caspase-3 activation; these observations correlated with restoration of the autophagy flux and memory improvement. This study highlights the importance of autophagic dysregulation in tauopathy and how administration of pharmacological doses of melatonin, once tauopathy is initiated, can restore the autophagy flux, reduce proteinopathy, and prevent cognitive decline. We therefore propose exogenous melatonin supplementation or the development of melatonin derivatives to improve autophagy flux for the treatment of proteinopathies like AD.

YY1 and FoxD3 regulate antiretroviral zinc finger protein OTK18 promoter activation induced by HIV-1 infection.

OTK18 is a C2H2 type zinc finger protein involved in the regulation of HIV-1 replication in human mononuclear phagocytes. Previously, we reported OTK18 expression in brain perivascular macrophages but not in microglia in HIV encephalitis brain. We have cloned the OTK18 promoter region proximal to the transcriptional start site and determined the region responsible (-884/+1) for the basal transcriptional activity in a microglia cell line. Sequential deletion mutation analyses reveal three important response elements: Yingyang-1 (YY1; -805/-777), an HIV-1 response element for promoter activation; FoxD3 (-743/-725), a negative regulatory element; and Ets response element (-725/-707), a basal transcriptional activity response element. HIV-1 infection-induced upregulation of YY1 and c-Ets-1 protein, binding to the promoter region as determined by immunoblotting and chromatin immunoprecipitation and polymerase chain reaction (PCR) assays, and induction of YY1 was also observed in virus-infected monocyte-derived macrophages. Silencing of FoxD3 and YY1 in the cell line by small interfering RNA duplexes specific to these molecules significantly up- and downregulated basal OTK18 promoter activity in FoxD3 and YY1 response element-dependent manners, respectively. On the other hand, infection of primary cultured human microglia significantly reduced YY1 expression and induced FoxD3 as determined by immunoblotting and reverse transcription real-time PCR. These data suggest that HIV-1 induces OTK18 expression through a YY1-mediated manner in human macrophages, although its gene expression is suppressed by FoxD3 upregulation and YY1 downregulation in human microglia. This mechanism may explain the perivascular macrophage-specific expression of OTK18 in HIV encephalitis brains.