Highlights d Described single-cell biophysical method for analyzing dark cone transduction noise d Dissected noise activity at each phototransduction step d Dark apo-opsin activity is, surprisingly, even higher than dark pigment activity

The isoforms of the APOE gene are of profound importance regarding the onset of Alzheimer's disease (AD), with APOE2 conferring resistance, APOE3 conferring neutral susceptibility, and APOE4 conferring proneness to AD. L-cysteine is an amino acid that has several anti-AD properties, among which are its ability to sequester iron and form glutathione (GSH), a powerful antioxidant. In our experiment, we fed Mus musculus (mice) homozygous for APOE2, APOE3, and APOE4 either a control diet or a diet high in L-cysteine. Using Western blotting analysis, we quantified total APOE proteins extracted from post-mortem brains of APOE2, APOE3, and APOE4 homozygous mice, total Amyloid β (Aβ) protein, and total hyper-phosphorylated Tau (HP-Tau) from mice at 3-, 6-, 9-, and 12-month ages. We found that administration of L-cysteine trends toward lowering levels of Aβ in the APOE3 cohort, but this effect is statistically insignificant. On the other hand, L-cysteine caused a significant increase in APOE4 abundance, but a significant decrease in APOE3 abundance regarding diet [F(6,42) = 5.61, p = 0.01]. Furthermore, administration of L-cysteine revealed trends toward lowering HP-Tau deposition in the APOE2 and APOE3 cohorts, but increasing deposition in the APOE4 cohort, although these effects are statistically insignificant. Moreover, immunohistochemistry analyses on the hippocampus and midsagittal brain revealed no effects of L-cysteine on Aβ. Results also showed a decrease in HP-Tau without regard to APOE genotype, but this was not statistically significant (p = 0.18). Taken together, these data suggest that L-cysteine may serve as a promising intervention for AD pathology, although future studies necessitate increasing statistical power to confirm the effect of diet on Aβ and HP-Tau deposition.

We propose that Alzheimer's disease (AD) progression is largely caused by excess reactive oxygen species (ROS) or free radicals created by iron dysregulation. An AD brain is struggling with damage control creating harmful tau tangles and amyloid plaques to deal with the dysregulated iron. We hypothesized that transgenic APP/PS1 (Amyloid precursor protein/ Presenilin-1) and Tau mice would exhibit higher levels of deposits in the brain which can be detected through MRI as well as decreased behavioral performance in radial arm maze tasks. We bred APP/PS1 transgenic mice overexpressing chimeric mouse/human APP-695 with mutations and human PSEN1 carrying the exon-9-deleted variant (PSEN1dE9), and Tau mice overexpressing all six isoforms of hyper-phosphorylated human MAPT (Microtubule associated protein Tau), which were compared with age controlled wild type mice. Mice received a diet of either regular or methionine rich chow as an oxidative stressor. Subgroups received a rescue treatment of either zinc, metformin or clioquinol chow. MRI (Magnetic Resonance Imaging) scans were performed using a Siemens 3 Tesla scanner. Behavioral data was collected using a radial arm maze (RAM) for 2 weeks at each point. Data collection time points were: 1 (baseline), 3, 6 and 9 months. Mean T2 TSE signals from scans on these mice revealed significant signal loss in bilateral hippocampi when compared by age. We also found a significant main effect of genotype and a trend toward significance for genotype and treatment interaction in the mean time mice spent in the RAM. Pairwise comparison showed a significant difference between the time male and female mice spent in the RAM. There was, however, no effect of signal loss or behavior deficit when comparing rescue treatments with or without oxidative insults. The decrease in signal and RAM performance is due to plaque increase and accompanying iron, which offers a possibility to refine the imaging techniques in pursuit of a noninvasive diagnostic biomarker.

Rod photoreceptors in the retina adjust their responsiveness and sensitivity so that they can continue to provide meaningful information over a wide range of light intensities. By stimulating membrane guanylate cyclases in the outer segment to synthesize cGMP at a faster rate in a Ca2+-dependent fashion, bicarbonate increases the circulating “dark” current and accelerates flash response kinetics in amphibian rods. Compared to amphibian rods, mammalian rods are smaller in size, operate at a higher temperature, and express visual cascade proteins with somewhat different biochemical properties. Here, we evaluated the role of bicarbonate in rods of cpfl3 mice. These mice are deficient in their expression of functional cone transducin, Gnat2, making cones very insensitive to light, so the rod response to light could be observed in isolation in electroretinogram recordings. Bicarbonate increased the dark current and absolute sensitivity and quickened flash response recovery in mouse rods to a greater extent than in amphibian rods. In addition, bicarbonate enabled mouse rods to respond over a range that extended to dimmer flashes. Larger flash responses may have resulted in part from a bicarbonate-induced elevation in intracellular pH. However, high pH alone had little effect on flash response recovery kinetics and even suppressed the accelerating effect of bicarbonate, consistent with a direct, modulatory action of bicarbonate on Ca2+- dependent, membrane guanylate cyclase activity.

Current theories regarding accumulation of Alzheimer's disease-related deposits of abnormal intra-and extracellular proteins include reactions to inflammation and mitochondrial dysfunction. In this study, we explored whether age, genotype and inflammation via diet have a greater effect on dysregulatory protein accumulation in any particular subfield of the hippocampus. We stained for ferritin, ferroportin, hyperphosphorylated tau and β-amyloid proteins in the hippocampal region of Apolipoprotein E2 (ApoE2), ApoE3 or ApoE4 mice fed a control diet or a hypothesized inflammationinducing methionine diet and euthanized at 3, 6, 9 or 12 months. We analysed stains based on hippocampal subfield and compared the protein accumulation levels within each group. We found significantly decreased ferritin expression in ApoE4 mice in the CA1 and Hi regions and decreased ferroportin expression in ApoE4 mice in the Hi region. There was also a significant effect on hyperphosphorylated tau protein levels based upon a given mouse genotype and diet interaction. Additionally, there were nonsignificant trends in each hippocampal subfield of increasing ferroportin and hyperphosphorylated tau after 6 months of age and decreasing β-amyloid and ferritin with age. This study identified that there are changes in iron regulatory molecules based on genotype in the Hi and CA1 regions. Our findings also suggest a diet-genotype interaction, which affects levels of specific Alzheimer's disease biomarkers in the hippocampus. Additionally, we identified a trend toward increased ability to clear β-amyloid and decreased ability to clear hyperphosphorylated tau with age in all subfields, in addition to evidence of increasing iron load with time.