Background and aims: The apolipoprotein E gene knockout (ApoE4) mouse is an excellent animal model for studying Alzheimer's disease pathology. ApoE-deficient (ApoED) and wild-type (WT) mice were tested for aging effects, including cerebral blood flow (CBF) as an indicator of vascular hypoperfusion, mitochondrial function and ultrastructural integrity, and cognitive tests, and for comparative amelioration from being fed acetyl-l-carnitine and R-alpha-lipoid acid (ALCAR+LA). Methods: CBF was measured using [14C] iodoantipyrene autoradiography in conjunction with a mathematical algorithm and an assumed arterial concentration profile derived from arterial concentration measurements; electron microscopy was employed to assess changes in neuronal, glial and microvascular ultrastructure and immunochemistry; and cognitive performance was determined using Morris Water Maze and Peak Procedure Test, with and without drug treatment (ALCAR, 0.2% (wt./vol.) in drinking water and LA, 0.1% (wt./wt.) in diet). Results: Compared to the WT mice, cortical blood flow (mean±SD, ml/g/min) was lowered significantly (p<0.05) in the ApoE-deficient mice in both the 6-month-(0.68±0.21 vs. 0.98±0.23) and 12-month-(1.06±0.09 vs. 1.54±0.12) old aged groups. In addition, 6-week-old ApoE-deficient mice had a lower cortical blood flow (0.63±0.15) in comparison to WT mice (0.82±0.15); however, differences did not reach statistical significance. Microvessels from ApoED mice showed vascular endothelial damage; significant overproliferation and deletion of the mitochondrial DNA and oxidative stress markers in endothelium and neurons were seen. ALCAR+LA treatment significantly improved cognitive performance and eliminated brain pathology in ApoE4 mice. Conclusions: Our data showed for the first time that ApoE deficiency appears to be a major factor in the age-dependent CBF reduction and brain cellular damage that is characteristic of AD pathology, which can be diminished by treating with selective mitochondrial antioxidants and/or their derivatives.

To maximize the light yield of the liquid scintillator (LS) for the Jiangmen Underground Neutrino Observatory (JUNO), a 20 t LS sample was produced in a pilot plant at Daya Bay. The optical properties of the new LS in various compositions were studied by replacing the gadolinium-loaded LS in one antineutrino detector. The concentrations of the fluor, PPO, and the wavelength shifter, bis-MSB, were increased in 12 steps from 0.5 g/L and <0.01 mg/L to 4 g/L and 13 mg/L, respectively. The numbers of total detected photoelectrons suggest that, with the optically purified solvent, the bis-MSB concentration does not need to be more than 4 mg/L. To bridge the one order of magnitude in the detector size difference between Daya Bay and JUNO, the Daya Bay data were used to tune the parameters of a newly developed optical model. Then, the model and tuned parameters were used in the JUNO simulation. This enabled to determine the optimal composition for the JUNO LS: purified solvent LAB with 2.5 g/L PPO, and 1 to 4 mg/L bis-MSB.

Transgenic mice carrying the E4 allele of apolipoprotein E gene related to Alzheimer's disease (AD) seem an excellent animal model for studying preclinical treatments of ApoE-related cognitive deficits because the animals express human ApoE4 at human levels in glia and exhibit measurable cognitive impairments. We investigated the role of age-dependent ApoE4 effects on cerebral blood flow (CBF) as an initiator of brain hypoperfusion using ApoE4 transgenic mice compared to age-matched wild-type (WT) mice using [C-14] iodoantipyrene autoradiography. ApoE4 associated factors reduces. CBF gradually to create brain hypoperfusion when compared to WT and the differences in CBF are greatest as animals age from 6-weeks to 12-months. Transmission electron microscopy and immunodecoration with colloidal gold immunocytochemistry showed that structural damage in young and aged microvessel endothelium of ApoE4 animals extended to the matrix of perivascular cells, perivascular nerve terminals and to hippocampal neurons and glial cells. Moreover, these abnormalities coexist with the mitochondrial structural alteration and mitochondrial DNA (mtDNA) overproliferation and/or deletion in all brain cellular compartments. Spatial memory and temporal memory tests showed a trend in improving cognitive function in ApoE4 mice fed acetyl-L-carnitine and R-lipoic acid (ALCAR+LA). Our findings indicate for the first time that the ApoE4 genotype induces mitochondrial changes and associated structural damage that may explain the age-dependent pathology seen in AD and potentially new and more effective treatment strategies in the near future.

Hypoxia-inducible factor-1 (HIF-1), a heterodimeric transcription factor consisting of HIF-1alpha and HIF-1beta subunits, controls the expression of a large number of genes involved in the regulation of cellular responses to reduced oxygen availability. The oxygen-regulated subunit, HIF-1alpha, is stabilized in cells exposed to hypoxia. The regulation of hypoxic responses by nitric oxide (NO) is believed to have wide pathophysiological relevance, thus we investigated whether NO affects HIF-1 activation in hypoxic cells. Here we show that NO generated from NO donors prevented HIF-1alpha hypoxic accumulation in Hep 3B and PC-12 cells. Addition of a glutathione analog or peroxynitrite scavengers prevented the NO-induced inhibition of HIF-1alpha accumulation in both cell lines. Exposure to NO was associated with inhibition of mitochondrial electron transport and compensatory glycolysis, which maintained normal cellular ATP content. Succinate, a Krebs cycle intermediate and respiratory chain substrate, restored HIF-1alpha hypoxic induction in the cells, suggesting involvement of mitochondria in regulation of HIF-1alpha accumulation during hypoxia. Regulation of HIF-1alpha by NO is an additional important mechanism by which NO might modulate cellular responses to hypoxia in mammalian cells.