Inhibition of Drp1 Ameliorates Synaptic Depression, Aß Deposition, and Cognitive Impairment in an Alzheimer's Disease Model.

Excessive mitochondrial fission is a prominent early event and contributes to mitochondrial dysfunction, synaptic failure, and neuronal cell death in the progression of Alzheimer's disease (AD). However, it remains to be determined whether inhibition of excessive mitochondrial fission is beneficial in mammal models of AD. To determine whether dynamin-related protein 1 (Drp1), a key regulator of mitochondrial fragmentation, can be a disease-modifying therapeutic target for AD, we examined the effects of Drp1 inhibitor on mitochondrial and synaptic dysfunctions induced by oligomeric amyloid-ß (Aß) in neurons and neuropathology and cognitive functions in Aß precursor protein/presenilin 1 double-transgenic AD mice. Inhibition of Drp1 alleviates mitochondrial fragmentation, loss of mitochondrial membrane potential, reactive oxygen species production, ATP reduction, and synaptic depression in Aß-treated neurons. Furthermore, Drp1 inhibition significantly improves learning and memory and prevents mitochondrial fragmentation, lipid peroxidation, BACE1 expression, and Aß deposition in the brain in the AD model. These results provide evidence that Drp1 plays an important role in Aß-mediated and AD-related neuropathology and in cognitive decline in an AD animal model. Therefore, inhibiting excessive Drp1-mediated mitochondrial fission may be an efficient therapeutic avenue for AD.SIGNIFICANCE STATEMENT Mitochondrial fission relies on the evolutionary conserved dynamin-related protein 1 (Drp1). Drp1 activity and mitochondria fragmentation are significantly elevated in the brains of sporadic Alzheimer's disease (AD) cases. In the present study, we first demonstrated that the inhibition of Drp1 restored amyloid-ß (Aß)-mediated mitochondrial dysfunctions and synaptic depression in neurons and significantly reduced lipid peroxidation, BACE1 expression, and Aß deposition in the brain of AD mice. As a result, memory deficits in AD mice were rescued by Drp1 inhibition. These results suggest that neuropathology and combined cognitive decline can be attributed to hyperactivation of Drp1 in the pathogenesis of AD. Therefore, inhibitors of excessive mitochondrial fission, such as Drp1 inhibitors, may be a new strategy for AD.

Pin1 promotes neuronal death in stroke by stabilizing Notch intracellular domain.

OBJECTIVE: Stroke is a leading cause of mortality and disability. The peptidyl-prolyl cis/trans isomerase Pin1 regulates factors involved in cell growth. Recent evidence has shown that Pin1 plays a major role in apoptosis. However, the role of Pin1 in ischemic stroke remains to be investigated. METHODS: We used Pin1 overexpression and knockdown to manipulate Pin1 expression and explore the effects of Pin1 in cell death on ischemic stress in vitro and in a mouse stroke model. We also used Pin 1 inhibitor, γ-secretase inhibitor, Notch1 intracellular domain (NICD1)-deleted mutant cells, and Pin1 mutant cells to investigate the underlying mechanisms of Pin1-NICD1-mediated cell death. RESULTS: Our findings indicate that Pin1 facilitates NICD1 stability and its proapoptotic function following ischemic stroke. Thus, overexpression of Pin1 increased NICD1 levels and enhanced its potentiation of neuronal death in simulated ischemia. By contrast, depletion or knockout of Pin1 reduced the NICD1 level, which in turn desensitized neurons to ischemic conditions. Pin1 interacted with NICD1 and increased its stability by inhibiting FBW7-induced polyubiquitination. We also demonstrate that Pin1 and NICD1 levels increase following stroke. Pin1 heterozygous (+/-) and knockout (-/-) mice, and also wild-type mice treated with an inhibitor of Pin1, each showed reduced brain damage and improved functional outcomes in a model of focal ischemic stroke. INTERPRETATION: These results suggest that Pin1 contributes to the pathogenesis of ischemic stroke by promoting Notch signaling, and that inhibition of Pin1 is a novel approach for treating ischemic stroke.

Down-regulation of mortalin exacerbates Aß-mediated mitochondrial fragmentation and dysfunction.

Mitochondrial dynamics greatly influence the biogenesis and morphology of mitochondria. Mitochondria are particularly important in neurons, which have a high demand for energy. Therefore, mitochondrial dysfunction is strongly associated with neurodegenerative diseases. Until now various post-translational modifications for mitochondrial dynamic proteins and several regulatory proteins have explained complex mitochondrial dynamics. However, the precise mechanism that coordinates these complex processes remains unclear. To further understand the regulatory machinery of mitochondrial dynamics, we screened a mitochondrial siRNA library and identified mortalin as a potential regulatory protein. Both genetic and chemical inhibition of mortalin strongly induced mitochondrial fragmentation and synergistically increased Aß-mediated cytotoxicity as well as mitochondrial dysfunction. Importantly we determined that the expression of mortalin in Alzheimer disease (AD) patients and in the triple transgenic-AD mouse model was considerably decreased. In contrast, overexpression of mortalin significantly suppressed Aß-mediated mitochondrial fragmentation and cell death. Taken together, our results suggest that down-regulation of mortalin may potentiate Aß-mediated mitochondrial fragmentation and dysfunction in AD.

Interaction of gaseous pollutants with aerosols in Asia during March 2002.

The Asian Dust Aerosol Model (ADAM) and the aerosol dynamic model with the output of the fifth generation of mesoscale model (MM5) in a grid of 60x60 km2 over the Asian domain have been performed with and without the heterogeneous reaction (gas-aerosol interaction) to estimate the effect of the gas-aerosol interaction on the formation of aerosol for the period of 1-31 March 2002 when a severe Asian dust event has been observed during this period. The simulated gas-phase pollutants concentrations and aerosols are compared with those observed in South Korea and the East Asia Network (EANET). The results indicate that the present modeling system including ADAM, aerosol dynamic model and MM5 model simulates quite well and the gas-phase pollutants concentrations observed in South Korea and the simulated aerosol concentrations with the gas-aerosol interaction yield much better results in concentrations than those without the gas-aerosol interaction. It is found that the favorable regions for the gas-aerosol interaction in Asia are eastern China (high pollutants emissions), Korea, Japan and the East China Sea that are downstream regions of the Asian dust sources and relatively high relative humidity. In these regions the concentrations of SO2 and O3 decrease whereas the concentrations of sulfate and nitrate increase significantly due to the gas-aerosol interaction. In particular, the increase of sulfate concentration due to the interaction is more than 30% of the corresponding concentration without the gas-aerosol interaction. It is also found that the time-area mean column concentrations of PM10, sulfate, nitrate in the model domain are respectively to be 154.9, 3.2, 3.6 mg m(-2) without the gas-aerosol interaction. However, with the gas-aerosol interaction these values have been increased to 0.6% (155.8 mg m(-2)), 16% (3.7 mg m(-2)), and 14% (4.1 mg m(-2)) of the corresponding concentration without the gas-aerosol interaction. On the other hand, the time-area mean concentration of ammonium is found to decrease about 13% (1.8 mg m(-2) to 1.6 mg m(-2)) due to the gas-aerosol interaction. The result clearly indicates the importance of the gas-aerosol interaction on the tropospheric chemistry during the long-range transport period.

Super anticorrosion of aluminized steel by a controlled Mg supply.

The current anticorrosion strategy makes use of coatings to passively protect the steel, which faces increasing challenge due to the tightened environmental regulations and high cost. This paper reports a new method for achieving a super anticorrosion function in Al-Si alloys through Mg nano-metallurgy, which was characterized by real-time synchrotron measurements. The unique function is based on the formation of an amorphous and self-charge-compensated MgAl2O4-SiO2 phase between the grain boundaries to help prevent the penetration of oxygen species through the grain boundaries. Through this, the corrosion resistance of pristine aluminized steel could be improved almost 20 fold. An analysis of the phases, microstructures of the Mg-coated aluminized layer and corrosion products consistently supported the proposed mechanism. This charge-compensated corrosion resistance mechanism provides novel insight into corrosion resistance.

A bimodal particle dynamics model considering coagulation, coalescence and surface growth, and its application to the growth of titania aggregates.

A simple bimodal particle dynamics model was proposed to describe a particle system undergoing simultaneous particle formation, coagulation, coalescence, and surface growth. We extended our previous bimodal model, which used two discrete modes, to account for the surface growth of nonspherical particles. Surface reaction from TiCl4 was considered and its effects on the formation and growth of TiO2 particles were investigated. Simulation results of the present bimodal model considering surface growth showed very good agreement with those of the moving sectional model for the growth of spherical TiO2 in the literature. Surface growth of TiO2 aggregates was also simulated by using this bimodal model and a new design diagram indicating the significance of surface reaction of TiCl4 was proposed.