Memory Deficits and Transcription Factor Activity Following Traumatic Brain Injury

Traumatic brain injury (TBI) is a serious condition and a leading cause of death and disability [1]. No two head injuries are alike and multiple complications are common in TBI. The most serious aspect of TBI is that of cognitive impairment as evidenced by animal and clinical studies focusing on synaptic plasticity and memory [2-5]. However, post trauma effects also includ

Inhibition of Hippocampal Synaptic Activity by ATP, Hypoxia or Oxygen-Glucose Deprivation Does Not Require CD73

Adenosine, through activation of its A1 receptors, has neuroprotective effects during hypoxia and ischemia. Recently, using transgenic mice with neuronal expression of human equilibrative nucleoside transporter 1 (hENT1), we reported that nucleoside transporter-mediated release of adenosine from neurons was not a key mechanism facilitating the actions of adenosine at A1 receptors during hypoxia/ischemia. The present study was performed to test the importance of CD73 (ecto-5′-nucleotidase) for basal and hypoxic/ischemic adenosine production. Hippocampal slice electrophysiology was performed with CD73+/+ and CD73−/− mice. Adenosine and ATP had similar inhibitory effects in both genotypes, with IC50 values of approximately 25 µM. In contrast, ATP was a less potent inhibitor (IC50 = 100 µM) in slices from mice expressing hENT1 in neurons. The inhibitory effects of ATP in CD73+/+ and CD73−/− slices were blocked by the adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) and were enhanced by the nucleoside transport inhibitor S-(4-nitrobenzyl)-6-thioinosine (NBTI), consistent with effects that are mediated by adenosine after metabolism of ATP. AMP showed a similar inhibitory effect to ATP and adenosine, indicating that the response to ATP was not mediated by P2 receptors. In comparing CD73−/− and CD73+/+ slices, hypoxia and oxygen-glucose deprivation produced similar depression of synaptic transmission in both genotypes. An inhibitor of tissue non-specific alkaline phosphatase (TNAP) was found to attenuate the inhibitory effects of AMP and ATP, increase basal synaptic activity and reduce responses to oxygen-glucose deprivation selectively in slices from CD73−/− mice. These results do not support an important role for CD73 in the formation of adenosine in the CA1 area of the hippocampus during basal, hypoxic or ischemic conditions, but instead point to TNAP as a potential source of extracellular adenosine when CD73 is absent

Nutrition state of science and dementia prevention: Recommendations of the Nutrition for Dementia Prevention Working Group

Observational studies suggest that nutritional factors have a potential cognitive benefit. However, systematic reviews of randomised trials of dietary and nutritional supplements have reported largely null effects on cognitive outcomes and have highlighted study inconsistencies and other limitations. In this Personal View, the Nutrition for Dementia Prevention Working Group presents what we consider to be limitations in the existing nutrition clinical trials for dementia prevention. On the basis of this evidence, we propose recommendations for incorporating dietary patterns and the use of genetic, and nutrition assessment tools, biomarkers, and novel clinical trial designs to guide future trial developments. Nutrition-based research has unique challenges that could require testing both more personalised interventions in targeted risk subgroups, identified by nutritional and other biomarkers, and large-scale and pragmatic study designs for more generalisable public health interventions across diverse populations

Alzheimers Dement

Disturbances in the brain's capacity to meet its energy demand increase the risk of synaptic loss, neurodegeneration, and cognitive decline. Nutritional and metabolic interventions that target metabolic pathways combined with diagnostics to identify deficits in cerebral bioenergetics may therefore offer novel therapeutic potential for Alzheimer's disease (AD) prevention and management. Many diet-derived natural bioactive components can govern cellular energy metabolism but their effects on brain aging are not clear. This review examines how nutritional metabolism can regulate brain bioenergetics and mitigate AD risk. We focus on leading mechanisms of cerebral bioenergetic breakdown in the aging brain at the cellular level, as well as the putative causes and consequences of disturbed bioenergetics, particularly at the blood-brain barrier with implications for nutrient brain delivery and nutritional interventions. Novel therapeutic nutrition approaches including diet patterns are provided, integrating studies of the gut microbiome, neuroimaging, and other biomarkers to guide future personalized nutritional interventions

Perspectives on ethnic and racial disparities in Alzheimer\u27s disease and related dementias: Update and areas of immediate need

Alzheimer\u27s disease and related dementias (ADRDs) are a global crisis facing the aging population and society as a whole. With the numbers of people with ADRDs predicted to rise dramatically across the world, the scientific community can no longer neglect the need for research focusing on ADRDs among underrepresented ethnoracial diverse groups. The Alzheimer\u27s Association International Society to Advance Alzheimer\u27s Research and Treatment (ISTAART; alz.org/ISTAART) comprises a number of professional interest areas (PIAs), each focusing on a major scientific area associated with ADRDs. We leverage the expertise of the existing international cadre of ISTAART scientists and experts to synthesize a cross-PIA white paper that provides both a concise “state-of-the-science” report of ethnoracial factors across PIA foci and updated recommendations to address immediate needs to advance ADRD science across ethnoracial populations. © 2018 The Author

Sex-based differences of a high fat diet in Alzheimer\u27s disease (AD): Can nilotinib reverse bioenergetic and neuropathological deficits?

ABSTRACT Metabolic disorders (i.e. obesity, prediabetes or type 2 diabetes), often resulting from poor diet, is a significant risk factor for Alzheimer’s disease (AD). Several common neurodegenerative mechanisms in these two conditions have been identified, including oxidative stress, mitochondrial dysfunction, and inflammation. Changes in metabolism and mitochondrial bioenergetics may be at the heart of both metabolic disorders and AD but may be affecting men and women differently. Although AD treatments exist, none are very effective, and certainly no drugs are sex-specific, creating a significant unmet medical need. Interestingly, several clinical trials testing nilotinib, a repurposed leukemia drug, have shown promise for use in treating AD and other neurodegenerative diseases. In addition to attenuating hallmark pathology, we recently demonstrated that nilotinib improves mitochondrial function and bioenergetics in cultured cells from the 3xTg-AD mouse model for AD. In this study, our specific objective is to use a high fat diet (HFD) to model metabolic disease in 3xTg-AD mice and evaluate sex-differences associated with bioenergetic, cognitive, and neuropathological outcomes, as well as whether nilotinib can improve them. The rationale for the proposed work is further supported by a recent phase II study conducted by our collaborator, Dr. Scott Turner, that showed 12 months of treatment with nilotinib, at 150 mg/day for 26 weeks followed by 300 mg/day for 26 weeks was safe, tolerable, and effective in patients with mild to moderate AD. Here, we hypothesize that nilotinib will improve mitochondrial bioenergetics, enhance cognitive function, and reduce biomarkers of AD pathology in a sex-dependent manner in 3xTg-AD mice subjected to a HFD. In Aim 1, we will determine whether in vivo treatment (100 or 250 mg/kg for 2 months) with nilotinib improves mitochondrial function and bioenergetics in 3xTg-AD mice in the absence and presence of HFD-induced metabolic disease. In Aim 2, we will investigate whether in vivo treatment with nilotinib can reverse cognitive-behavioral deficits in 3xTg-AD mice in the absence and presence of metabolic disease. Finally, in Aim 3, we will characterize the effects of in vivo treatment with nilotinib on AD-associated neuropathology in 3xTg-AD mice in the absence and presence of metabolic disease. The mechanisms by which nilotinib may improve outcomes in vivo, as well as patient populations for whom nilotinib treatment may be safe and effective (i.e., based on sex and comorbid metabolic disease, present in 80% of AD patients), have yet to be adequately explored in rodent models prior to the commencement of the drug’s phase III trial. We expect that a HFD will result in a wider range of bioenergetic, cognitive, and neuropathological consequences in female AD mice as compared to males. Overall, we expect nilotinib will improve mitochondrial function, ATP levels, AD-associated neuropathology, and cognition in 3xTg AD mice, including those subjected to a HFD

Oscillations and NMDA Receptors: Their Interplay Create Memories

Oscillatory activity is inherent in many types of normal cellular function. Importantly, oscillations contribute to cellular network activity and cellular decision making, which are driving forces for cognition. Theta oscillations have been correlated with learning and memory encoding and gamma oscillations have been associated with attention and working memory. NMDA receptors are also implicated in oscillatory activity and contribute to normal function and in disease-related pathology. The interplay between oscillatory activity and NMDA receptors are intellectually curious and a fascinating dimension of inquiry. In this review we introduce some of the essential mathematical characteristics of oscillatory activity in order to provide a platform for additional discussion on recent studies concerning oscillations involving neuronal firing and NMDA receptor activity, and the effect of these dynamic mechanisms on cognitive processing in health and disease