Alterations of High-Energy Brain Metabolites Across Multiple Neurodegenerative Disorders

Brain energy metabolism is vital for many cellular processes including homeostasis and thus disturbances to metabolism can be the cause or consequence of neurodegeneration. Metabolic discrepancies have been hypothesized to be involved but less frequently demonstrated to be manipulated by acute and chronic neurodegenerative disorders such as stroke, traumatic brain injury, and epilepsy. I hypothesized that cerebral energy levels are decreased in my model systems for Alzheimer\u27s disease, Autism, Down syndrome, and HIV-1 dementia and that dietary treatments could enhance energy reserves and protect against neurodegenerative disease. For rodent studies, I utlilized a high-energy head focused microwave irradiation system to kill animals but most importantly to snap-inactivate all cerebral enzymes, including those that contribute to the rapid degradation of high-energy phosphate compounds. I found that energy levels are diminished in a high-cholesterol diet model for Alzheimer\u27s disease in rabbit, a trisomic mouse model for Down syndrome (Ts65Dn), and following administration of Tat to primary mouse cortical cultures as a model for HIV-1 dementia. My experiments also examined the extent to which protection is provided by creatine supplementation and the ketogenic diet in models of HIV-1 dementia and epilepsy, respectively. Creatine bioenergetically protected against Tat-induced decreases in cellular levels of ATP, Tat-induced mitochondrial hypopolarization, and Tat-induced mitochondrial permeability transition pore opening. My calorie restricted ketogenic diet studies demonstrated this diet\u27s ability to protect against chemically induced seizures. As well, I observed a coordinated upregulation of all differentially regulated transcripts encoding energy metabolism enzymes, increased numbers of mitochondrial profiles, and ultimately augmented high-energy phosphate levels in seizure naïve rats. My studies demonstrate compromised brain energy levels in the aforementioned neurodegenerative disorders and that dietary treatments such as creatine supplementation for HIV-1 dementia and the ketogenic diet for epilepsy, may protect cerebral function by enhancing neuroenergetics

Caffeine blocks disruption of blood brain barrier in a rabbit model of Alzheimer's disease

High levels of serum cholesterol and disruptions of the blood brain barrier (BBB) have all been implicated as underlying mechanisms in the pathogenesis of Alzheimer's disease. Results from studies conducted in animals and humans suggest that caffeine might be protective against Alzheimer's disease but by poorly understood mechanisms. Using rabbits fed a cholesterol-enriched diet, we tested our hypothesis that chronic ingestion of caffeine protects against high cholesterol diet-induced disruptions of the BBB. New Zealand rabbits were fed a 2% cholesterol-enriched diet, and 3 mg caffeine was administered daily in drinking water for 12 weeks. Total cholesterol and caffeine concentrations from blood were measured. Olfactory bulbs (and for some studies hippocampus and cerebral cortex as well) were evaluated for BBB leakage, BBB tight junction protein expression levels, activation of astrocytes, and microglia density using histological, immunostaining and immunoblotting techniques. We found that caffeine blocked high cholesterol diet-induced increases in extravasation of IgG and fibrinogen, increases in leakage of Evan's blue dye, decreases in levels of the tight junction proteins occludin and ZO-1, increases in astrocytes activation and microglia density where IgG extravasation was present. Chronic ingestion of caffeine protects against high cholesterol diet-induced increases in disruptions of the BBB, and caffeine and drugs similar to caffeine might be useful in the treatment of Alzheimer's disease

Proteomic analysis of six- and twelve-month hippocampus and cerebellum in a murine Down syndrome model

This study was designed to investigate the brain proteome of the Ts65Dn mouse model of Down syndrome. We profiled the cerebellum and hippocampus proteomes of 6- and 12-month-old trisomic and disomic mice by difference gel electrophoresis. We quantified levels of 2082 protein spots and identified 272 (170 unique UniProt accessions) by mass spectrometry. Four identified proteins are encoded by genes trisomic in the Ts65Dn mouse. Three of these (CRYZL11, EZR, and SOD1) were elevated with p-value \u3c0.05, and 2 proteins encoded by disomic genes (MAPRE3 and PHB) were reduced. Intergel comparisons based on age (6 vs. 12 months) and brain region (cerebellum vs. hippocampus) revealed numerous differences. Specifically, 132 identified proteins were different between age groups, and 141 identified proteins were different between the 2 brain regions. Our results suggest that compensatory mechanisms exist, which ameliorate the effect of trisomy in the Ts65Dn mice. Differences observed during aging may play a role in the accelerated deterioration of learning and memory seen in Ts65Dn mice

Many Labs 5:Testing pre-data collection peer review as an intervention to increase replicability

Replication studies in psychological science sometimes fail to reproduce prior findings. If these studies use methods that are unfaithful to the original study or ineffective in eliciting the phenomenon of interest, then a failure to replicate may be a failure of the protocol rather than a challenge to the original finding. Formal pre-data-collection peer review by experts may address shortcomings and increase replicability rates. We selected 10 replication studies from the Reproducibility Project: Psychology (RP:P; Open Science Collaboration, 2015) for which the original authors had expressed concerns about the replication designs before data collection; only one of these studies had yielded a statistically significant effect (p < .05). Commenters suggested that lack of adherence to expert review and low-powered tests were the reasons that most of these RP:P studies failed to replicate the original effects. We revised the replication protocols and received formal peer review prior to conducting new replication studies. We administered the RP:P and revised protocols in multiple laboratories (median number of laboratories per original study = 6.5, range = 3?9; median total sample = 1,279.5, range = 276?3,512) for high-powered tests of each original finding with both protocols. Overall, following the preregistered analysis plan, we found that the revised protocols produced effect sizes similar to those of the RP:P protocols (?r = .002 or .014, depending on analytic approach). The median effect size for the revised protocols (r = .05) was similar to that of the RP:P protocols (r = .04) and the original RP:P replications (r = .11), and smaller than that of the original studies (r = .37). Analysis of the cumulative evidence across the original studies and the corresponding three replication attempts provided very precise estimates of the 10 tested effects and indicated that their effect sizes (median r = .07, range = .00?.15) were 78% smaller, on average, than the original effect sizes (median r = .37, range = .19?.50)

A multi-country test of brief reappraisal interventions on emotions during the COVID-19 pandemic.

The COVID-19 pandemic has increased negative emotions and decreased positive emotions globally. Left unchecked, these emotional changes might have a wide array of adverse impacts. To reduce negative emotions and increase positive emotions, we tested the effectiveness of reappraisal, an emotion-regulation strategy that modifies how one thinks about a situation. Participants from 87 countries and regions (n = 21,644) were randomly assigned to one of two brief reappraisal interventions (reconstrual or repurposing) or one of two control conditions (active or passive). Results revealed that both reappraisal interventions (vesus both control conditions) consistently reduced negative emotions and increased positive emotions across different measures. Reconstrual and repurposing interventions had similar effects. Importantly, planned exploratory analyses indicated that reappraisal interventions did not reduce intentions to practice preventive health behaviours. The findings demonstrate the viability of creating scalable, low-cost interventions for use around the world

Caffeine blocks disruption of blood brain barrier in a rabbit model of Alzheimer's disease-1

His effect was blocked by caffeine at the dose of 3 mg/day. Caffeine alone had no effect on extravasation of fibrinogen in normal rabbit brain. Representative images taken from 2 rabbits in each group with 6 sections from each animal are shown. Bar = 50 μm. (B) Cholesterol-enriched diet significantly increased accumulation of fibrinogen in olfactory bulb and this effect was blocked by caffeine at the dose of 3 mg/day. (C) Neither cholesterol-enriched diet nor caffeine changed significantly plasma levels of fibrinogen. n = 4, *p < 0.05.<p><b>Copyright information:</b></p><p>Taken from "Caffeine blocks disruption of blood brain barrier in a rabbit model of Alzheimer's disease"</p><p>http://www.jneuroinflammation.com/content/5/1/12</p><p>Journal of Neuroinflammation 2008;5():12-12.</p><p>Published online 3 Apr 2008</p><p>PMCID:PMC2330033.</p><p></p

Caffeine blocks disruption of blood brain barrier in a rabbit model of Alzheimer's disease-7

Hed diet markedly increased the numbers of microglia (green, arrow heads) and IgG extravasation (red). These effects were blocked by caffeine at the dose of 3 mg/day for 12 weeks. Representative images taken from 2 rabbits in each group with 6 sections from each animal are shown. Bar = 50 μm. (B) In a magnified view of the white boxes as shown in panel A, increased microglia (arrow heads) are co-distributed with perivascular immunopositive IgG staining (arrows) in olfactory bulb from cholesterol-fed rabbits. Bar = 20 μm.<p><b>Copyright information:</b></p><p>Taken from "Caffeine blocks disruption of blood brain barrier in a rabbit model of Alzheimer's disease"</p><p>http://www.jneuroinflammation.com/content/5/1/12</p><p>Journal of Neuroinflammation 2008;5():12-12.</p><p>Published online 3 Apr 2008</p><p>PMCID:PMC2330033.</p><p></p

Caffeine blocks disruption of blood brain barrier in a rabbit model of Alzheimer's disease-6

Und the sites where IgG extravasation (red) was present. These effects were blocked by caffeine at the dose of 3 mg/day. Representative images taken from 2 rabbits in each group with 6 sections from each animal are shown. Bar = 20 μm.<p><b>Copyright information:</b></p><p>Taken from "Caffeine blocks disruption of blood brain barrier in a rabbit model of Alzheimer's disease"</p><p>http://www.jneuroinflammation.com/content/5/1/12</p><p>Journal of Neuroinflammation 2008;5():12-12.</p><p>Published online 3 Apr 2008</p><p>PMCID:PMC2330033.</p><p></p

Caffeine blocks disruption of blood brain barrier in a rabbit model of Alzheimer's disease-0

Ect was blocked by caffeine at the dose of 3 mg/day. Caffeine alone had no effect on extravasation of IgG in normal rabbit brain. Representative images taken from 2 rabbits in each group with 6 sections from each animal are shown. Bar = 50 μm. (B) Cholesterol-enriched diet significantly increased accumulation of IgG in olfactory bulb and this effect was blocked by caffeine at the dose of 3 mg/day. (C) Neither cholesterol-enriched diet nor caffeine changed significantly plasma levels of IgG. n = 4, *p < 0.05.<p><b>Copyright information:</b></p><p>Taken from "Caffeine blocks disruption of blood brain barrier in a rabbit model of Alzheimer's disease"</p><p>http://www.jneuroinflammation.com/content/5/1/12</p><p>Journal of Neuroinflammation 2008;5():12-12.</p><p>Published online 3 Apr 2008</p><p>PMCID:PMC2330033.</p><p></p

Caffeine blocks disruption of blood brain barrier in a rabbit model of Alzheimer's disease-4

) at the sites where IgG extravasation (red) was present. These effects were blocked by chronic ingestion of caffeine. Representative images taken from 2 rabbits in each group with 6 sections from each animal are shown. Bar = 20 μm.<p><b>Copyright information:</b></p><p>Taken from "Caffeine blocks disruption of blood brain barrier in a rabbit model of Alzheimer's disease"</p><p>http://www.jneuroinflammation.com/content/5/1/12</p><p>Journal of Neuroinflammation 2008;5():12-12.</p><p>Published online 3 Apr 2008</p><p>PMCID:PMC2330033.</p><p></p