Search

Recent studies have demonstrated a potential role for oligomeric forms of amyloid-β (Aβ) in the pathogenesis of Alzheimer's disease (AD), although it remains unclear which aspects of AD may be mediated by oligomeric Aβ. In the present study, we found that primary cultures of rat cortical neurons exhibit a dose-dependent increase in cell death following Aβ oligomer administration, while primary cultures of astrocytes exhibited no overt toxicity with even the highest concentrations of oligomer treatment. Neither cell type exhibited toxicity when treated by equal concentrations of monomeric Aβ. The neuron death induced by oligomer treatment was associated with an increase in reactive oxygen species (ROS), altered expression of mitochondrial fission and fusion proteins, and JUN kinase activation. Pharmacological inhibition of JUN kinase ameliorated oligomeric Aβ toxicity in neurons. These data indicate that oligomeric Aβ is sufficient to selectively induce toxicity in neurons, but not astrocytes, with neuron death occurring in a JUN kinase-dependent manner. Additionally, these observations implicate a role for oligomeric Aβ as a contributor to neuronal oxidative stress and mitochondrial disturbances in AD. [ABSTRACT FROM AUTHOR]

Herbal remedies are increasing in popularity as treatments for metabolic conditions such as obesity and Type 2 Diabetes. One potential therapeutic option is fenugreek seeds ( Trigonella foenum-graecum ), which have been used for treating high cholesterol and Type 2 diabetes. A proposed mechanism for these benefits is through alterations in the microbiome, which impact mammalian host metabolic function. This study used untargeted metabolomics to investigate the fenugreek-induced alterations in the intestinal, liver, and serum profiles of mice fed either a 60% high-fat or low-fat control diet each with or without fenugreek supplementation (2% w / w ) for 14 weeks. Metagenomic analyses of intestinal contents found significant alterations in the relative composition of the gut microbiome resulting from fenugreek supplementation. Specifically, Verrucomicrobia, a phylum containing beneficial bacteria which are correlated with health benefits, increased in relative abundance with fenugreek. Metabolomics partial least squares discriminant analysis revealed substantial fenugreek-induced changes in the large intestines. However, it was observed that while the magnitude of changes was less, significant modifications were present in the liver tissues resulting from fenugreek supplementation. Further analyses revealed metabolic processes affected by fenugreek and showed broad ranging impacts in multiple pathways, including carnitine biosynthesis, cholesterol and bile acid metabolism, and arginine biosynthesis. These pathways may play important roles in the beneficial effects of fenugreek.

Fenugreek (Trigonella foenum-graecum) is an annual herbaceous plant and a staple of traditional health remedies for metabolic conditions including high cholesterol and diabetes. While the mechanisms of the beneficial actions of fenugreek remain unknown, a role for intestinal microbiota in metabolic homeostasis is likely. To determine if fenugreek utilizes intestinal bacteria to offset the adverse effects of high fat diets, C57BL/6J mice were fed control/low fat (CD) or high fat (HFD) diets each supplemented with or without 2% (w/w) fenugreek for 16 weeks. The effects of fenugreek and HFD on gut microbiota were comprehensively mapped and then statistically assessed in relation to effects on metrics of body weight, hyperlipidemia, and glucose tolerance. 16S metagenomic analyses revealed robust and significant effects of fenugreek on gut microbiota, with alterations in both alpha and beta diversity as well as taxonomic redistribution under both CD and HFD conditions. As previously reported, fenugreek attenuated HFD-induced hyperlipidemia and stabilized glucose tolerance without affecting body weight. Finally, fenugreek specifically reversed the dysbiotic effects of HFD on numerous taxa in a manner tightly correlated with overall metabolic function. Collectively, these data reinforce the essential link between gut microbiota and metabolic syndrome and suggest that the preservation of healthy populations of gut microbiota participates in the beneficial properties of fenugreek in the context of modern Western-style diets.

Alzheimer's disease (AD) is the most common age-related neurodegenerative disease, while obesity is a major global public health problem associated with the metabolic disorder type 2 diabetes mellitus (T2DM). Chronic obesity and T2DM have been identified as invariant risk factors for dementia and late-onset AD, while their impacts on the occurrence and development of AD remain unclear. As shown in our previous study, the diabetic mutation (db, Lepr db/db ) induces mixed or vascular dementia in mature to middle-aged APP ΔNL/ΔNL x PS1 P264L/P264L knock-in mice (db/AD). In the present study, the impacts of the db mutation on young AD mice at 10 weeks of age were evaluated. The db mutation not only conferred young AD mice with severe obesity, impaired glucose regulation and activated mammalian target of rapamycin (mTOR) signaling pathway in the mouse cortex, but lead to a surprising improvement in memory. At this young age, mice also had decreased cerebral Aβ content, which we have not observed at older ages. This was unlikely to be related to altered Aβ synthesis, as both β- and γ-secretase were unchanged. The db mutation also reduced the cortical IL-1β mRNA level and IBA1 protein level in young AD mice, with no significant effect on the activation of microglia and astrocytes. We conclude that the db mutation could transitorily improve the memory of young AD mice, a finding that may be partially explained by the relatively improved glucose homeostasis in the brains of db/AD mice compared to their counterpart AD mice, suggesting that glucose regulation could be a strategy for prevention and treatment of neurodegenerative diseases like AD., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The gut microbiota has emerged as a critical player in shaping and modulating brain function and has been shown to influence numerous behaviors, including anxiety and depression-like behaviors, sociability, and cognition. However, the effects of the gut microbiota on specific disorders associated with thalamo-cortico-basal ganglia circuits, ranging from compulsive behavior and addiction to altered sensation and motor output, are only recently being explored. Wholesale depletion and alteration of gut microbial communities in rodent models of disorders, such as Parkinson's disease, autism, and addiction, robustly affect movement and motivated behavior. A new frontier therefore lies in identifying specific microbial alterations that affect these behaviors and understanding the underlying mechanisms of action. Comparing alterations in gut microbiota across multiple basal-ganglia associated disease states allows for identification of common mechanistic pathways that may interact with distinct environmental and genetic risk factors to produce disease-specific outcomes., (Copyright © 2018 the authors 0270-6474/18/389414-09$15.00/0.)

Background: Clarifying relationships between specific neurocognitive functions in cognitively intact older adults can improve our understanding of mechanisms involved in cognitive decline, which may allow identification of new opportunities for intervention and earlier detection of those at increased risk of dementia., Method: The present study employed latent growth curve modeling to longitudinally examine the relationship between executive attention/processing speed, episodic memory, language, and working memory functioning utilizing the neuropsychological test battery from the National Alzheimer's Disease Coordinating Center. A total of 691 relatively healthy older adults (M age  = 69.07, SD = 6.49) were assessed at baseline, and 553 individuals completed three visits spanning a two-year period., Results: Better cognitive performance was concomitantly associated with better functioning across domains. Subtle declines in executive attention/processing speed processes were found, while, on average, memory and language performance improved with repeated testing. Lower executive attention/processing speed performance at baseline predicted less incremental growth rate in memory. In turn, higher initial memory functioning was associated with incremental improvements in language performance., Conclusions: These results are consistent with the notion that intact executive function and attention processes are important to preserving memory functioning with advanced age, but are also the functions most susceptible to decline with age. These findings also provide further insight into the critical role of practice effects in clinical assessment practice and have implications for pharmaceutical trials. Practice effects should be routinely considered as they may give the appearance of retention of function within the cognitive domains considered to be a hallmark of Alzheimer's disease pathology.

There has been an explosion of interest in the study of microorganisms inhabiting the gastrointestinal tract (gut microbiota) and their impact on host health and physiology. Accumulating data suggest that altered communication between gut microbiota and host systems could participate in disorders such as obesity, diabetes mellitus, and autoimmune disorders as well as neuropsychiatric disorders, including autism, anxiety, and major depressive disorders. The conceptual development of the microbiome-gut-brain axis has facilitated understanding of the complex and bidirectional networks between gastrointestinal microbiota and their host, highlighting potential mechanisms through which this environment influences central nervous system physiology. Communication pathways between gut microbiota and the central nervous system could include autonomic, neuroendocrine, enteric, and immune systems, with pathology resulting in disruption to neurotransmitter balance, increases in chronic inflammation, or exacerbated hypothalamic-pituitary-adrenal axis activity. However, uncertainty remains regarding the generalizability of controlled animal studies to the more multifaceted pattern of human pathophysiology, especially with regard to the therapeutic potential for neuropsychiatric health. This narrative review summarizes current understanding of gut microbial influence over physiological function, with an emphasis on neurobehavioral and neurological impairment based on growing understanding of the gut-brain axis. Experimental and clinical data regarding means of therapeutic manipulation of gut microbiota as a novel treatment option for mental health are described, and important knowledge gaps are identified and discussed., (Copyright © 2017. Published by Elsevier Inc.)

High fat diet-induced obesity is associated with inflammatory and oxidative signaling in macrophages that likely participates in metabolic and physiologic impairment. One key factor that could drive pathologic changes in macrophages is the pro-inflammatory, pro-oxidant enzyme NADPH oxidase. However, NADPH oxidase is a pleiotropic enzyme with both pathologic and physiologic functions, ruling out indiscriminant NADPH oxidase inhibition as a viable therapy. To determine if targeted inhibition of monocyte/macrophage NADPH oxidase could mitigate obesity pathology, we generated mice that lack the NADPH oxidase catalytic subunit NOX2 in myeloid lineage cells. C57Bl/6 control (NOX2-FL) and myeloid-deficient NOX2 (mNOX2-KO) mice were given high fat diet for 16 weeks, and subject to comprehensive metabolic, behavioral, and biochemical analyses. Data show that mNOX2-KO mice had lower body weight, delayed adiposity, attenuated visceral inflammation, and decreased macrophage infiltration and cell injury in visceral adipose relative to control NOX2-FL mice. Moreover, the effects of high fat diet on glucose regulation and circulating lipids were attenuated in mNOX2-KO mice. Finally, memory was impaired and markers of brain injury increased in NOX2-FL, but not mNOX2-KO mice. Collectively, these data indicate that NOX2 signaling in macrophages participates in the pathogenesis of obesity, and reinforce a key role for macrophage inflammation in diet-induced metabolic and neurologic decline. Development of macrophage/immune-specific NOX-based therapies could thus potentially be used to preserve metabolic and neurologic function in the context of obesity.

Maternal obesity is known to predispose offspring to metabolic and neurodevelopmental abnormalities. While the mechanisms underlying these phenomena are unclear, high fat diets dramatically alter intestinal microbiota, and gut microbiota can impact physiological function. To determine if maternal diet-induced gut dysbiosis can disrupt offspring neurobehavioral function, we transplanted high fat diet- (HFD) or control low fat diet-associated (CD) gut microbiota to conventionally-housed female mice. Recipient mice were then bred and the behavioral phenotype of male and female offspring was tracked. While maternal behavior was unaffected, neonatal offspring from HFD dams vocalized less upon maternal separation than pups from CD dams. Furthermore, weaned male offspring from HFD dams had significant and selective disruptions in exploratory, cognitive, and stereotypical/compulsive behavior compared to male offspring from CD dams; while female offspring from HFD dams had increases in body weight and adiposity. 16S metagenomic analyses confirmed establishment of divergent microbiota in CD and HFD dams, with alterations in diversity and taxonomic distribution throughout pregnancy and lactation. Likewise, significant alterations in gut microbial diversity and distribution were noted in offspring from HFD dams compared to CD dams, and in males compared to females. Regression analyses of behavioral performance against differentially represented taxa suggest that decreased representation of specific members of the Firmicutes phylum predict behavioral decline in male offspring. Collectively, these data establish that high fat diet-induced maternal dysbiosis is sufficient to disrupt behavioral function in murine offspring in a sex-specific manner. Thus these data reinforce the essential link between maternal diet and neurologic programming in offspring and suggest that intestinal dysbiosis could link unhealthy modern diets to the increased prevalence of neurodevelopmental and childhood disorders.

Nuclear factor E2-related factor 2 (NRF2) is a well-known master controller of the cellular adaptive antioxidant and detoxification response. Recent studies demonstrated altered glucose, lipid and energy metabolism in mice with a global Nrf2 knockout. In the present study, we aim to determine the effects of an adipose-specific ablation of Nrf2 (ASAN) on diet-induced obesity (DIO) in male mice. The 6-week-old adipose-specific Nrf2 knockout (NK) and its Nrf2 control (NC) mice were fed with either control diet (CD) or high-fat diet (HFD) for 14 weeks. NK mice exhibited transiently delayed body weight (BW) growth from week 5 to week 11 of HFD feeding, higher daily physical activity levels and preferential use of fat over carbohydrates as a source of energy at week 8 of the CD-feeding period. After 14 weeks of feeding, NK mice showed comparable results with NC mice with respect to the overall BW and body fat content, but exhibited reduced blood glucose, reduced number but increased size of adipocytes, accompanied with elevated expression of many genes and proteins in the visceral fat related to glucose, lipid and energy metabolism (e.g. Fgf21 , Pgc1a ). These results indicated that NRF2 is an important mediator for glucose, lipid and energy metabolism in adipose tissue, and ASAN could have beneficial effect for prevention of DIO during the early development of mice.

Background: Developing measures to detect preclinical Alzheimer's Disease is vital, as prodromal stage interventions may prove more efficacious in altering the disease's trajectory. Gait changes may serve as a useful clinical heuristic that precedes cognitive decline. This study provides the first systematic investigation of gait characteristics relationship with relevant demographic, physical, genetic (Apolipoprotein E genotype), and health risk factors in non-demented older adults during a cognitive-load dual task walking condition., Methods: The GAITRite system provided objective measurement of gait characteristics in APOE-e4 "carriers" (n = 75) and "non-carriers" (n = 224). Analyses examined stride length and step time gait characteristics during simple and dual-task (spelling five-letter words backwards) conditions in relation to demographic, physical, genetic, and health risk factors., Results: Slower step time and shorter stride length associated with older age, greater health risk, and worse physical performance (ps < .05). Men and women differed in height, gait characteristics, health risk factors and global cognition (ps < .05). APOE-e4 associated with a higher likelihood of hypercholesterolemia and overall illness index scores (ps < .05). No genotype-sex interactions on gait were found. APOE-e4 was linked to shorter stride length and greater dual-task related disturbances in stride length., Conclusions: Stride length has been linked to heightened fall risk, attention decrements and structural brain changes in older adults. Our results indicate that stride length is a useful behavioral marker of cognitive change that is associated with genetic risk for AD. Sex disparities in motor decline may be a function of health risk factors.

Ghrelin is an orexigenic hormone with a role in the onset and progression of neurodegenerative disorders. It has been recently associated to Alzheimer's disease (AD) for its neuroprotective and anti-apoptotic activity. In the present study, we dissected the effect of ghrelin treatment on the two major intracellular proteolytic pathways, the ubiquitin-proteasome system (UPS) and autophagy, in cellular models of AD (namely SH-SY5Y neuroblastoma cells stably transfected with either the wild-type AβPP gene or the 717 valine-to-glycine AβPP-mutated gene). Ghrelin showed a growth-promoting effect on neuronal cells inducing also time-dependent modifications of the growth hormone secretagogue receptor type 1 (GHS-R1) expression. Interestingly, we demonstrated for the first time that ghrelin was able to activate the proteasome in neural cells playing also a role in the interplay between the UPS and autophagy. Our data provide a novel mechanism by which circulating hormones control neural homeostasis through the regulation of proteolytic pathways implicated in AD.

HIV protease inhibitors are key components of HIV antiretroviral therapies, which are fundamental in the treatment of HIV infection. However, the protease inhibitors are well-known to induce metabolic dysfunction which can in turn escalate the complications of HIV, including HIV associated neurocognitive disorders. As experimental and epidemiological data support a therapeutic role for adiponectin in both metabolic and neurologic homeostasis, this study was designed to determine if increased adiponectin could prevent the detrimental effects of protease inhibitors in mice. Adult male wild type (WT) and adiponectin-overexpressing (ADTg) mice were thus subjected to a 4-week regimen of lopinavir/ritonavir, followed by comprehensive metabolic, neurobehavioral, and neurochemical analyses. Data show that lopinavir/ritonavir-induced lipodystrophy, hypoadiponectinemia, hyperglycemia, hyperinsulinemia, and hypertriglyceridemia were attenuated in ADTg mice. Furthermore, cognitive function and blood-brain barrier integrity were preserved, while loss of cerebrovascular markers and white matter injury were prevented in ADTg mice. Finally, lopinavir/ritonavir caused significant increases in expression of markers of brain inflammation and decreases in synaptic markers in WT, but not in ADTg mice. Collectively, these data reinforce the pathophysiologic link from metabolic dysfunction to loss of cerebrovascular and cognitive homeostasis; and suggest that preservation and/or replacement of adiponectin could prevent these key aspects of HIV protease inhibitor-induced toxicity in clinical settings., (Copyright © 2016. Published by Elsevier B.V.)

Recent clinical and laboratory evidences suggest that high fat diet (HFD) induced obesity and its associated metabolic syndrome conditions promotes neuropathology in aging and age-related neurological disorders. However, the effects of high fat diet on brain pathology are poorly understood, and the effective strategies to overcome these effects remain elusive. In the current study, we examined the effects of HFD on brain pathology and further evaluated whether donepezil, an AChE inhibitor with neuroprotective functions, could suppress the ongoing HFD induced pathological changes in the brain. Our data demonstrates that HFD induced obesity results in increased neuroinflammation and increased AChE activity in the brain when compared with the mice fed on low fat diet (LFD). HFD administration to mice activated mTOR pathway resulting in increased phosphorylation of mTOR(ser2448), AKT(thr308) and S6K proteins involved in the signaling. Interestingly, donepezil administration with HFD suppressed HFD induced increases in AChE activity, and partially reversed HFD effects on microglial reactivity and the levels of mTOR signaling proteins in the brain when compared to the mice on LFD alone. However, gross levels of synaptic proteins were not altered in the brain tissues of mice fed either diet with or without donepezil. In conclusion, these results present a new insight into the detrimental effects of HFD on brain via microglial activation and involvement of mTOR pathway, and further demonstrates the possible therapeutic role for donepezil in ameliorating the early effects of HFD that could help preserve the brain function in metabolic syndrome conditions., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Despite effective viral suppression through combined antiretroviral therapy (cART), approximately half of HIV-positive individuals have HIV-associated neurocognitive disorders (HAND). Studies of antiretroviral-treated patients have revealed persistent white matter abnormalities including diffuse myelin pallor, diminished white matter tracts, and decreased myelin protein mRNAs. Loss of myelin can contribute to neurocognitive dysfunction because the myelin membrane generated by oligodendrocytes is essential for rapid signal transduction and axonal maintenance. We hypothesized that myelin changes in HAND are partly due to effects of antiretroviral drugs on oligodendrocyte survival and/or maturation. We showed that primary mouse oligodendrocyte precursor cell cultures treated with therapeutic concentrations of HIV protease inhibitors ritonavir or lopinavir displayed dose-dependent decreases in oligodendrocyte maturation; however, this effect was rapidly reversed after drug removal. Conversely, nucleoside reverse transcriptase inhibitor zidovudine had no effect. Furthermore, in vivo ritonavir administration to adult mice reduced frontal cortex myelin protein levels. Finally, prefrontal cortex tissue from HIV-positive individuals with HAND on cART showed a significant decrease in myelin basic protein compared with untreated HIV-positive individuals with HAND or HIV-negative controls. These findings demonstrate that antiretrovirals can impact myelin integrity and have implications for myelination in juvenile HIV patients and myelin maintenance in adults on lifelong therapy.

Background: The prevalence of mental illness, particularly depression and dementia, is increased by obesity. Here, we test the hypothesis that obesity-associated changes in gut microbiota are intrinsically able to impair neurocognitive behavior in mice., Methods: Conventionally housed, nonobese, adult male C57BL/6 mice maintained on a normal chow diet were subjected to a microbiome depletion/transplantation paradigm using microbiota isolated from donors on either a high-fat diet (HFD) or control diet. Following re-colonization, mice were subjected to comprehensive behavioral and biochemical analyses., Results: The mice given HFD microbiota had significant and selective disruptions in exploratory, cognitive, and stereotypical behavior compared with mice with control diet microbiota in the absence of significant differences in body weight. Sequencing-based phylogenetic analysis confirmed the presence of distinct core microbiota between groups, with alterations in α- and β-diversity, modulation in taxonomic distribution, and statistically significant alterations to metabolically active taxa. HFD microbiota also disrupted markers of intestinal barrier function, increased circulating endotoxin, and increased lymphocyte expression of ionized calcium-binding adapter molecule 1, toll-like receptor 2, and toll-like receptor 4. Finally, evaluation of brain homogenates revealed that HFD-shaped microbiota increased neuroinflammation and disrupted cerebrovascular homeostasis., Conclusions: Collectively, these data reinforce the link between gut dysbiosis and neurologic dysfunction and suggest that dietary and/or pharmacologic manipulation of gut microbiota could attenuate the neurologic complications of obesity., (Copyright © 2015 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Gait abnormalities are linked to cognitive decline and an increased fall risk within older adults. The present study addressed gaps from cross-sectional studies in the literature by longitudinally examining the interplay between temporal and spatial aspects of gait, cognitive function, age, and lower-extremity strength in elderly "fallers" and "non-fallers". Gait characteristics, neuropsychological and physical test performance were examined at two time points spaced a year apart in cognitively intact individuals aged 60 and older (N = 416). Mixed-model repeated-measure ANCOVAs examined temporal (step time) and spatial (stride length) gait characteristics during a simple and cognitive-load walking task in fallers as compared to non-fallers. Fallers consistently demonstrated significant alterations in spatial, but not temporal, aspects of gait as compared to non-fallers during both walking tasks. Step time became slower as stride length shortened amongst all participants during the dual task. Shorter strides and slower step times during the dual task were both predicted by worse executive attention/processing speed performance. In summary, divided attention significantly impacts spatial aspects of gait in "fallers", suggesting stride length changes may precede declines in other neuropsychological and gait characteristics, thereby selectively increasing fall risk. Our results indicate that multimodal intervention approaches that integrate physical and cognitive remediation strategies may increase the effectiveness of fall risk interventions.

Neuropsychological abilities have found to explain a large proportion of variance in objective measures of walking gait that predict both dementia and falling within the elderly. However, to this date there has been little research on the interplay between changes in these neuropsychological processes and walking gait overtime. To our knowledge, the present study is the first to investigate intra-individual changes in neurocognitive test performance and gait step time at two-time points across a one-year span. Neuropsychological test scores from 440 elderly individuals deemed cognitively normal at Year One were analyzed via repeated measures t-tests to assess for decline in cognitive performance at Year Two. 34 of these 440 individuals neuropsychological test performance significantly declined at Year Two; whereas the "non-decliners" displayed improved memory, working memory, attention/processing speed test performance. Neuropsychological test scores were also submitted to factor analysis at both time points for data reduction purposes and to assess the factor stability overtime. Results at Year One yielded a three-factor solution: Language/Memory, Executive Attention/Processing Speed, and Working Memory. Year Two's test scores also generated a three-factor solution (Working Memory, Language/Executive Attention/Processing Speed, and Memory). Notably, language measures loaded on Executive Attention/Processing Speed rather than on the Memory factor at Year Two. Hierarchal multiple regression revealed that both Executive Attention/Processing Speed and sex significantly predicted variance in dual task step time at both time points. Remarkably, in the "decliners", the magnitude of the contribution of the neuropsychological characteristics to gait variance significantly increased at Year Two. In summary, this study provides longitudinal evidence of the dynamic relationship between intra-individual cognitive change and its influence on dual task gait step time. These results also indicate that the failure to show improved test performance (particularly, on memory tests) with repeated administrations might prove to be useful of indicator of early cognitive decline.

HIV protease inhibitors (PI) are fundamental to combination antiretroviral therapy, which has revolutionized HIV clinical care and produced significant reductions in HIV-associated morbidity and mortality. However, PI administration is frequently associated with severe metabolic impairment, including lipodystrophy, dyslipidemia, and insulin resistance; all of which can contribute to cardiovascular and neurologic co-morbidities. Experimental and epidemiological data support a potentially important role for the adipokine adiponectin in both metabolic and neurologic physiology. This study examined if ADP355, a novel, peptide-based adiponectin receptor agonist, could neutralize the detrimental effects of PI treatment in experimental animal models. Adult male C57BL/6 mice were subjected to a clinically relevant, 4-week regimen of lopinavir/ritonavir, with daily injections of ADP355 administered only during the final 2 weeks of PI exposure. Comprehensive metabolic, neurobehavioral, and biochemical analyses revealed that ADP355 administration partially reversed PI-induced loss of subcutaneous adipose tissue, attenuated PI-induced hyperinsulinemia, hypertriglyceridemia, and hypoadiponectinemia, and prevented PI-induced cognitive impairment and brain injury. Collectively, these data reinforce the link between metabolic co-morbidities and cognitive impairment and suggest that pharmacological reactivation of adiponectin pathways could remediate key aspects of PI-induced metabolic syndrome in clinical settings. Furthermore, therapeutic targeting of adiponectin receptors could show utility in reducing the prevalence and/or severity of HIV-associated neurocognitive disorders.

Cerebral amyloid angiopathy (CAA) occurs in nearly every individual with Alzheimer's disease (AD) and Down's syndrome, and is the second largest cause of intracerebral hemorrhage. Mouse models of CAA have demonstrated evidence for increased gliosis contributing to CAA pathology. Nearly two thirds of Americans are overweight or obese, with little known about the effects of obesity on the brain, although increasingly the vasculature appears to be a principle target of obesity effects on the brain. In the current study we describe for the first time whether diet induced obesity (DIO) modulates glial reactivity, amyloid levels, and inflammatory signaling in a mouse model of CAA. In these studies we identify surprisingly that DIO does not significantly increase Aβ levels, astrocyte (GFAP) or microglial (IBA-1) gliosis in the CAA mice. However, within the hippocampal gyri a localized increase in reactive microglia were increased in the CA1 and stratum oriens relative to CAA mice on a control diet. DIO was observed to selectively increase IL-6 in CAA mice, with IL-1β and TNF-α not increased in CAA mice in response to DIO. Taken together, these data show that prolonged DIO has only modest effects towards Aβ in a mouse model of CAA, but appears to elevate some localized microglial reactivity within the hippocampal gyri and selective markers of inflammatory signaling. These data are consistent with the majority of the existing literature in other models of Aβ pathology, which surprisingly show a mixed profile of DIO effects towards pathological processes in mouse models of neurodegenerative disease. The importance for considering the potential impact of ceiling effects in pathology within mouse models of Aβ pathogenesis, and the current experimental limitations for DIO in mice to fully replicate metabolic dysfunction present in human obesity, are discussed. This article is part of a Special Issue entitled: Animal Models of Disease., (Copyright © 2012. Published by Elsevier B.V.)

While considerable knowledge has been gained through the use of established cognitive and motor assessment tools, there is a considerable interest and need for the development of a battery of reliable and validated assessment tools that provide real-time and remote analysis of cognitive and motor function in the elderly. Smartphones appear to be an obvious choice for the development of these "next-generation" assessment tools for geriatric research, although to date no studies have reported on the use of smartphone-based applications for the study of cognition in the elderly. The primary focus of the current study was to assess the feasibility, reliability, and validity of a smartphone-based application for the assessment of cognitive function in the elderly. A total of 57 non-demented elderly individuals were administered a newly developed smartphone application-based Color-Shape Test (CST) in order to determine its utility in measuring cognitive processing speed in the elderly. Validity of this novel cognitive task was assessed by correlating performance on the CST with scores on widely accepted assessments of cognitive function. Scores on the CST were significantly correlated with global cognition (Mini-Mental State Exam: r = 0.515, p<0.0001) and multiple measures of processing speed and attention (Digit Span: r = 0.427, p<0.0001; Trail Making Test: r = -0.651, p<0.00001; Digit Symbol Test: r = 0.508, p<0.0001). The CST was not correlated with naming and verbal fluency tasks (Boston Naming Test, Vegetable/Animal Naming) or memory tasks (Logical Memory Test). Test re-test reliability was observed to be significant (r = 0.726; p = 0.02). Together, these data are the first to demonstrate the feasibility, reliability, and validity of using a smartphone-based application for the purpose of assessing cognitive function in the elderly. The importance of these findings for the establishment of smartphone-based assessment batteries of cognitive and motor function in the elderly is discussed.

Nearly two-thirds of the population in the United States is overweight or obese, and this unprecedented level of obesity will undoubtedly have a profound impact on overall health, although little is currently known about the effects of obesity on the brain. The objective of this study was to investigate cerebral oxidative stress and cognitive decline in the context of diet-induced obesity (DIO). We demonstrate for the first time that DIO induces higher levels of reactive oxygen species (ROS) in the brain and promotes cognitive impairment. Importantly, we also demonstrate for the first time in these studies that both body weight and adiposity are tightly correlated with the level of ROS. Interestingly, ROS were not correlated with cognitive decline in this model. Alterations in the antioxidant/detoxification Nrf2 pathway, superoxide dismutase, and catalase activity levels were not significantly altered in response to DIO. However, a significant impairment in glutathione peroxidase was observed in response to DIO. Taken together, these data demonstrate for the first time that DIO increases the levels of total and individual ROS in the brain and highlight a direct relationship between the amount of adiposity and the level of oxidative stress within the brain. These data have important implications for understanding the negative effects of obesity on the brain and are vital to understanding the role of oxidative stress in mediating the effects of obesity on the brain., (Published by Elsevier Inc.)

Alzheimer's disease (AD) is the most common age-related neurodegenerative disease, affecting an estimated 5.3million people in the United States. While many factors likely contribute to AD progression, it is widely accepted that AD is driven by the accumulation of β-amyloid (Aβ), a small, fibrillogenic peptide generated by the sequential proteolysis of the amyloid precursor protein by the β- and γ-secretases. Though the underlying causes of Aβ accumulation in sporadic AD are myriad, it is clear that lifestyle and overall health play a significant role. The adipocyte-derived hormone leptin has varied systemic affects, including neuropeptide release and neuroprotection. A recent study by Lieb et al. (2009) showed that individuals with low plasma leptin levels are at greater risk of developing AD, through unknown mechanisms. In this report, we show that plasma leptin is a strong negative predictor of Aβ levels in the mouse brain, supporting a protective role for the hormone in AD onset. We also show that the inhibition of Aβ accumulation is due to the downregulation of transcription of the γ-secretase components. On the other hand, β-secretase expression is either unchanged (BACE1) or increased (BACE2). Finally, we show that only presenilin 1 (PS1) is negatively correlated with plasma leptin at the protein level (p<0.0001). These data are intriguing and may highlight a role for leptin in regulating the onset of amyloid pathology and AD., (Copyright © 2013 Elsevier B.V. All rights reserved.)

The consumption of high-fat/calorie diets in modern societies is likely a major contributor to the obesity epidemic, which can increase the prevalence of cancer, cardiovascular disease, and neurological impairment. Obesity may precipitate decline via inflammatory and oxidative signaling, and one factor linking inflammation to oxidative stress is the proinflammatory, pro-oxidant enzyme NADPH oxidase. To reveal the role of NADPH oxidase in the metabolic and neurological consequences of obesity, the effects of high-fat diet were compared in wild-type C57Bl/6 (WT) mice and in mice deficient in the NAPDH oxidase subunit NOX2 (NOX2KO). While diet-induced weight gains in WT and NOX2KO mice were similar, NOX2KO mice had smaller visceral adipose deposits, attenuated visceral adipocyte hypertrophy, and diminished visceral adipose macrophage infiltration. Moreover, the detrimental effects of HFD on markers of adipocyte function and injury were attenuated in NOX2KO mice; NOX2KO mice had improved glucose regulation, and evaluation of NOX2 expression identified macrophages as the primary population of NOX2-positive cells in visceral adipose. Finally, brain injury was assessed using markers of cerebrovascular integrity, synaptic density, and reactive gliosis, and data show that high-fat diet disrupted marker expression in WT but not NOX2KO mice. Collectively, these data indicate that NOX2 is a significant contributor to the pathogenic effects of high-fat diet and reinforce a key role for visceral adipose inflammation in metabolic and neurological decline. Development of NOX-based therapies could accordingly preserve metabolic and neurological function in the context of metabolic syndrome.

Lipid peroxidation products such as 4-hydroxynonenal (HNE) are known to be increased in response to oxidative stress, and are known to cause dysfunction and pathology in a variety of tissues during periods of oxidative stress. The aim of the current study was to determine the chronic (repeated HNE exposure) and acute effects of physiological concentrations of HNE toward multiple aspects of adipocyte biology using differentiated 3T3-L1 adipocytes. Our studies demonstrate that acute and repeated exposure of adipocytes to physiological concentrations of HNE is sufficient to promote subsequent oxidative stress, impaired adipogenesis, alter the expression of adipokines, and increase lipolytic gene expression and subsequent increase in free fatty acid (FFA) release. These results provide an insight in to the role of HNE-induced oxidative stress in regulation of adipocyte differentiation and adipose dysfunction. Taken together, these data indicate a potential role for HNE promoting diverse effects toward adipocyte homeostasis and adipocyte differentiation, which may be important to the pathogenesis observed in obesity and metabolic syndrome.

HIV-associated neurocognitive disorders (HAND) remain prevalent even with widespread use of combination antiretroviral therapy (ART), suggesting a potential role for co-morbidities in neurologic decline. Indeed, it is well established that ART drugs, particularly HIV protease inhibitors, can induce hyperlipidemia, lipodystrophy, and insulin resistance; all of which are associated with neurologic impairment. This study was designed to determine how metabolic dysfunction might contribute to cognitive impairment and to reveal specific metabolic co-morbidities that could be targeted to preserve brain function. Adult male C57BL/6 mice were thus treated with clinically relevant doses of lopinavir/ritonavir for 4 weeks, and subjected to thorough metabolic, neurobehavioral, and biochemical analyses. Data show that lopinavir/ritonavir resulted in manifestations of lipodystrophy, insulin resistance, and hyperlipidemia. Evaluation of neurologic function revealed cognitive impairment and increased learned helplessness, but not motor impairment following treatment with lopinavir/ritonavir. Further analyses revealed a significant linear relationship between cognitive performance and specific markers of lipodystrophy and insulin resistance. Finally, analysis of brain injury indicated that lopinavir/ritonavir treatment resulted in cerebrovascular injury associated with decreased synaptic markers and increased inflammation, and that the cerebral cortex was more vulnerable than the cerebellum or hippocampus. Collectively, these data reveal an intimate link between metabolic co-morbidities and cognitive impairment, and suggest that remediation of selective aspects of metabolic syndrome could potentially reduce the prevalence or severity HIV-associated neurocognitive disorders., (Copyright © 2012 Elsevier B.V. All rights reserved.)

This study describes the effects of long-chain fatty acids on inflammatory signaling in cultured astrocytes. Data show that the saturated fatty acid palmitic acid, as well as lauric acid and stearic acid, trigger the release of TNFα and IL-6 from astrocytes. Unsaturated fatty acids were unable to induce cytokine release from cultured astrocytes. Furthermore, the effects of palmitic acid on cytokine release require Toll-like receptor 4 rather than CD36 or Toll-like receptor 2, and do not depend on palmitic acid metabolism to palmitoyl-CoA. Inhibitor studies revealed that pharmacologic inhibition of p38 or p42/44 MAPK pathways prevents the pro-inflammatory effects of palmitic acid, whereas JNK and PI3K inhibition does not affect cytokine release. Depletion of microglia from primary astrocyte cultures using the lysosomotropic agent l-leucine methyl ester revealed that the ability of palmitic acid to trigger cytokine release is not dependent on the presence of microglia. Finally, data show that the essential ω-3 fatty acid docosahexaenoic acid acts in a dose-dependent manner to prevent the actions of palmitic acid on inflammatory signaling in astrocytes. Collectively, these data demonstrate the ability of saturated fatty acids to induce astrocyte inflammation in vitro. These data thus raise the possibility that high levels of circulating saturated fatty acids could cause reactive gliosis and brain inflammation in vivo, and could potentially participate in the reported adverse neurologic consequences of obesity and metabolic syndrome., (© 2012 The Authors. Journal of Neurochemistry © 2012 International Society for Neurochemistry.)

Mutations in amyloid precursor protein (APP) have been most intensely studied in brain tissue for their link to Alzheimer's disease (AD) pathology. However, APP is highly expressed in a variety of tissues including adipose tissue, where APP is also known to exhibit increased expression in response to obesity. In our current study, we analyzed the effects of mutant APP (E693Q, D694N, K670N/M671L) expression toward multiple aspects of adipose tissue homeostasis. These data reveal significant hypoleptinemia, decreased adiposity, and reduced adipocyte size in response to mutant APP, and this was fully reversed upon high fat diet administration. Additionally, mutant APP was observed to significantly exacerbate insulin resistance, triglyceride elevations, and macrophage infiltration of adipose tissue in response to a high fat diet. Taken together, these data have significant implications for linking mutant APP expression to adipose tissue dysfunction and global changes in endocrine and metabolic function under both obesogenic and non-obesogenic conditions.

Cognitive impairment in Alzheimer's disease (AD) is strongly associated with both extensive deposition of amyloid β peptides and oxidative stress, but the exact role of these indices in the development of dementia is not clear. This study was designed to determine the relationship between cognitive impairment, activation of the free radical producing enzyme NADPH oxidase (NOX), and progressive changes in Aβ deposition and solubility in humanized APP×PS1 knock-in mice of increasing age. Data show that cognitive performance and expression of key synaptic proteins were progressively decreased in aging APP×PS1 mice. Likewise, NOX activity and expression of the specific NOX subunit NOX4 were significantly increased in APP×PS1 mice in an age-dependent manner, and NOX activity and cognitive impairment shared a significant linear relationship. Data further show that age-dependent increases in Aβ(1-42) had a significant linear relationship with both NOX activity and cognitive performance in APP×PS1 knock-in mice. Collectively, these data show that NOX expression and activity are significantly upregulated with age in this humanized model of Aβ pathogenesis, and suggest that NOX-associated redox pathways are intimately linked to both the loss of cognitive function and the deposition of Aβ(1-42)., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Intracellular proteins are degraded by a number of proteases, including the ubiquitin-proteasome pathway (UPP). Impairments in the UPP occur during the aging of a variety of tissues, although little is known in regards to age-related alterations to the UPP during the aging of adipose tissue. The UPP is known to be involved in regulating the differentiation of a variety of cell types, although the potential changes in the UPP during adipose differentiation have not been fully elucidated. How the UPP is altered in aging adipose tissue and adipocyte differentiation and the effects of proteasome inhibition on adipocyte homeostasis and differentiation are critical issues to elucidate experimentally. Adipogenesis continues throughout the life of adipose tissue, with continual differentiation of preadipocytes essential to maintaining tissue function during aging, and UPP alterations in mature adipocytes are likely to directly modulate adipose function during aging. In this study we demonstrate that aging induces alterations in the activity and expression of principal components of the UPP. Additionally, we show that multiple changes in the UPP occur during the differentiation of 3T3-L1 cells into adipocytes. In vitro data link observed UPP alterations to increased levels of oxidative stress and altered adipose biology relevant to both aging and differentiation. Taken together, these data demonstrate that changes in the UPP occur in response to adipose aging and adipogenesis and strongly suggest that proteasome inhibition is sufficient to decrease adipose differentiation, as well as increasing oxidative stress in mature adipocytes, both of which probably promote deleterious effects on adipose aging., (Published by Elsevier Inc.)

As a part of aging there are known to be numerous alterations which occur in multiple tissues of the body, and the focus of this study was to determine the extent to which oxidative stress and hypoxia occur during adipose tissue aging. In our studies we demonstrate for the first time that aging is associated with both hypoxia (38% reduction in oxygen levels, Po(2) 21.7 mmHg) and increases reactive oxygen species in visceral fat depots of aging male C57Bl/6 mice. Interestingly, aging visceral fat depots were observed to have significantly less change in the expression of genes involved in redox regulation compared with aging subcutaneous fat tissue. Exposure of 3T3-L1 adipocytes to the levels of hypoxia observed in aging adipose tissue was sufficient to alter multiple aspects of adipose biology inducing increased levels of in insulin-stimulated glucose uptake and decreased lipid content. Taken together, these data demonstrate that hypoxia and increased levels of reactive oxygen species occur in aging adipose tissue, highlighting the potential for these two stressors as potential modulators of adipose dysfunction during aging.

Amino acid analogs promote translational errors that result in aberrant protein synthesis and have been used to understand the effects of protein misfolding in a variety of physiological and pathological settings. TDP-43 is a protein that is linked to protein aggregation and toxicity in a variety of neurodegenerative diseases. This study exposed primary rat neurons and astrocyte cultures to established amino acid analogs (canavanine and azetidine-2-carboxylic acid) and showed that both cell types undergo a dose-dependent increase in toxicity, with neurons exhibiting a greater degree of toxicity compared with astrocytes. Neurons and astrocytes exhibited similar increases in ubiquitinated and oxidized protein following analog treatment. Analog treatment increased heat shock protein (Hsp) levels in both neurons and astrocytes. In neurons, and to a lesser extent astrocytes, the levels of TDP-43 increased in response to analog treatment. Taken together, these data indicate that neurons exhibit preferential toxicity and alterations in TDP-43 in response to increased protein misfolding compared with astrocytes., (Copyright © 2011 Wiley-Liss, Inc.)

It is well established that HIV antiretroviral drugs, particularly protease inhibitors, frequently elicit a metabolic syndrome that may include hyperlipidemia, lipodystrophy, and insulin resistance. Metabolic dysfunction in non-HIV-infected subjects has been repeatedly associated with cognitive impairment in epidemiological and experimental studies, but it is not yet understood if antiretroviral therapy-induced metabolic syndrome might contribute to HIV-associated neurologic decline. To determine if protease inhibitor-induced metabolic dysfunction in mice is accompanied by adverse neurologic effects, C57BL/6 mice were given combined lopinavir/ritonavir (50/12.5-200/50 mg/kg) daily for 3 weeks. Data show that lopinavir/ritonavir administration caused significant metabolic derangement, including alterations in body weight and fat mass, as well as dose-dependent patterns of hyperlipidemia, hypoadiponectinemia, hypoleptinemia, and hyperinsulinemia. Evaluation of neurologic function revealed that even the lowest dose of lopinavir/ritonavir caused significant cognitive impairment assessed in multi-unit T-maze, but did not affect motor functions assessed as rotarod performance. Collectively, our results indicate that repeated lopinavir/ritonavir administration produces cognitive as well as metabolic impairments, and suggest that the development of selective aspects of metabolic syndrome in HIV patients could contribute to HIV-associated neurocognitive disorders., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Excitotoxicity and/or microglial reactivity might underlie neurologic dysfunction in HIV patients. The HIV regulatory protein Tat is both neurotoxic and pro-inflammatory, suggesting that Tat might participate in the pathogenesis of HIV-associated neurocognitive disorders (HAND). The present study was undertaken to evaluate if Tat can increase extracellular glutamate, and was specifically designed to determine the degree to which, and the mechanisms by which Tat could drive microglial glutamate release. Data show that application of Tat to cultured primary microglia caused dose-dependent increases in extracellular glutamate that were exacerbated by morphine, which is known to worsen Tat cytotoxicity. Tat-induced glutamate release was decreased by inhibitors of p38 and p42/44 MAPK, and by inhibitors of NADPH oxidase and the x(c)(-) cystine-glutamate antiporter. Furthermore, Tat increased expression of the catalytic subunit of x(c)(-) (xCT), but Tat-induced increases in xCT mRNA were not affected by inhibition of NADPH oxidase or x(c)(-) activity. Together, these data describe a specific and biologically significant signaling component of the microglial response to Tat, and suggest that excitotoxic neuropathology associated with HIV infection might originate in part with Tat-induced activation of microglial glutamate release., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Long term consumption of a high fat diet (HFD) contributes to increased morbidity and mortality. Yet the specific effects of HFD consumption on brain aging are poorly understood. In the present study 20-month old male C57Bl/6 mice were fed either 'western diet' (41% fat), very high fat lard diet (60% fat), or corresponding control diets for 16 weeks and then assessed for changes in metabolism and brain homeostasis. Although both HFDs increased adiposity and fasting blood glucose, only the high fat lard diet increased age-related oxidative damage (protein carbonyls) and impaired retention in the behavioral test. This selective increase in oxidative damage and cognitive decline was also associated with a decline in NF-E2-related factor 2 (Nrf2) levels and Nrf2 activity, suggesting a potential role for decreased antioxidant response. Taken together, these data suggest that while adiposity and insulin resistance following HFD consumption are linked to increased morbidity, the relationship between these factors and brain homeostasis during aging is not a linear relationship. More specifically, these data implicate impaired Nrf2 signaling and increased cerebral oxidative stress as mechanisms underlying HFD-induced declines in cognitive performance in the aged brain., (© 2010 The Authors. Journal Compilation © 2010 International Society for Neurochemistry.)

This study describes how age and high fat diet affect the profile of NADPH oxidase (NOX). Specifically, NOX activity and subunit expression were evaluated in the frontal cerebral cortex of 7-, 16-, and 24-month old mice following a 4-month exposure to either Western diet (WD, 41% calories from fat) or very high fat lard diet (VHFD, 60% calories from fat). Data reveal a significant effect of age in on NOX activity, and show that NOX activity was only increased by VHFD, and only in 24-month old mice. NOX subunit expression was also increased by diet only in older mice. Quantification of protein carbonyls revealed significant age-related increases in protein oxidation, and indicate that only aged mice respond to high fat diet with enhanced protein oxidation. Histological analyses indicate prominent neuronal localization of both NOX subunits and protein carbonylation. Finally, data indicate that changes in reactive microgliosis, but not astrocytosis, mirror the pattern of diet-induced NOX activation and protein oxidation. Collectively, these data show that both age and dietary fat drive NOX activation, and further indicate that aged mice are preferentially sensitive to the effects of high fat diet. These data also suggest that high fat diets might exacerbate age-related oxidative stress in the brain via increased NOX., ((c) 2010 Elsevier Inc. All rights reserved.)

Deleterious neurochemical, structural, and behavioral alterations are a seemingly unavoidable aspect of brain aging. However, the basis for these alterations, as well as the basis for the tremendous variability in regards to the degree to which these aspects are altered in aging individuals, remains to be elucidated. An increasing number of individuals regularly consume a diet high in fat, with high-fat diet consumption known to be sufficient to promote metabolic dysfunction, although the links between high-fat diet consumption and aging are only now beginning to be elucidated. In this review we discuss the potential role for age-related metabolic disturbances serving as an important basis for deleterious perturbations in the aging brain. These data not only have important implications for understanding the basis of brain aging, but also may be important to the development of therapeutic interventions which promote successful brain aging.

This study was undertaken to investigate the profile of NADPH oxidase (NOX) in the clinical progression of Alzheimer's disease (AD). Specifically, NOX activity and expression of the regulatory subunit p47phox and the catalytic subunit gp91phox was evaluated in affected (superior and middle temporal gyri) and unaffected (cerebellum) brain regions from a longitudinally followed group of patients. This group included both control and late-stage AD subjects, and also subjects with preclinical AD and with amnestic mild cognitive impairment (MCI) to evaluate the profile of NOX in the earliest stages of dementia. Data show significant elevations in NOX activity and expression in the temporal gyri of MCI patients as compared with controls, but not in preclinical or late-stage AD samples, and not in the cerebellum. Immunohistochemical evaluations of NOX expression indicate that whereas microglia express high levels of gp91phox, moderate levels of gp91phox also are expressed in neurons. Finally, in vitro experiments showed that NOX inhibition blunted the ability of oligomeric amyloid beta peptides to injure cultured neurons. Collectively, these data show that NOX expression and activity are upregulated specifically in a vulnerable brain region of MCI patients, and suggest that increases in NOX-associated redox pathways in neurons might participate in the early pathogenesis of AD.

Increased levels of misfolded and damaged proteins occur in response to brain aging and Alzheimer disease (AD), which presumably increase the amount of aggregation-prone proteins via elevations in hydrophobicity. The proteasome is an intracellular protease that degrades oxidized and ubiquitinated proteins, and its function is known to be impaired in response to both aging and AD. In this study we sought to determine the potential for increased levels of protein hydrophobicity occurring in response to aging and AD, to identify the contribution of proteasome inhibition to increased protein hydrophobicity, and last to identify the contribution of ubiquitinated and oxidized proteins to the pool of hydrophobic proteins. In our studies we identified that aging and AD brain exhibited increases in protein hydrophobicity as detected using Bis ANS, with dietary restriction (DR) significantly decreasing age-related increases in protein hydrophobicity. Affinity chromatography purification of hydrophobic proteins from aging and AD brains identified increased levels of oxidized and ubiquitinated proteins in the pool of hydrophobic proteins. Pharmacological inhibition of the proteasome in neurons, but not astrocytes, resulted in an increase in protein hydrophobicity. Taken together, these data indicate that there is a relationship between increased protein oxidation and protein ubiquitination and elevations in protein hydrophobicity within the aging and the AD brain, which may be mediated in part by impaired proteasome activity in neurons. Our studies also suggest a potential role for decreased oxidized and hydrophobic proteins in mediating the beneficial effects of DR., (Published by Elsevier Inc.)

C57Bl/6 mice were administered a high fat, Western diet (WD, 41% fat) or a very high fat lard diet (HFL, 60% fat), and evaluated for cognitive ability using the Stone T-maze and for biochemical markers of brain inflammation. WD consumption resulted in significantly increased body weight and astrocyte reactivity, but not impaired cognition, microglial reactivity, or heightened cytokine levels. HFL increased body weight, and impaired cognition, increased brain inflammation, and decreased BDNF. Collectively, these data suggest that while different diet formulations can increase body weight, the ability of high fat diets to disrupt cognition is linked to brain inflammation., (Copyright 2009 Elsevier B.V. All rights reserved.)

Inhibition of the proteasome proteolytic pathway occurs as the result of normal aging, as well as in a variety of neurodegenerative conditions, and is believed to promote cellular toxicity in each of these conditions through diverse mechanisms. In the present study, we examined whether proteasome inhibition alters the protein kinase receptor-like endoplasmic reticulum kinase (PERK). Our studies demonstrate that proteasome inhibitors induce the transient activation of PERK in both primary rat neurons as well as the N2a neural cell line. Experiments with siRNA to PERK demonstrated that the modulation of PERK was not significant involved in regulating toxicity, ubiquitinated protein levels, or ribosome perturbations in response to proteasome inhibitor treatment. Surprisingly, PERK was observed to be involved in the up-regulation of p38 kinase following proteasome inhibitor treatment. Taken together, these data demonstrate the ability of proteasome inhibition to activate PERK and demonstrate evidence for novel cross-talk between PERK and the activation of p38 kinase in neural cells following proteasome inhibition. Taken together, these data have implications for understanding the basis by which proteasome inhibition alters neural homeostasis, and the basis by which cell signaling cascades are regulated by proteasome inhibition.

In this study we examined whether established signal transduction cascades, p44/42 mitogen-activated protein kinase (ERK1/2) and Jun N-terminal kinases (JNK) pathways, are altered in N2a neural cells in response to proteasome inhibition. Additionally, we sought to elucidate the relative contribution of these signal transduction pathways to the multiple downstream effects of proteasome inhibition. Our data indicate that ERK1/2 and JNK are activated in response to proteasome inhibition. Washout of proteasome inhibitor (MG132) results in an enhancement of ERK1/2 activation and amelioration of JNK activation. Treatment with an established MAPK inhibitor resulted in an increase in proteasome inhibitor toxicity, and incubation with JNK inhibitor was observed to attenuate proteasome inhibitor toxicity significantly. Subsequent studies demonstrated that inhibition of ERK1/2 and JNK activity does not alter the gross increase in ubiquitinated protein following proteasome inhibitor administration. Similarly, ERK1/2 and JNK activity do not appear to play a role in the disruption of polysomes following proteasome inhibitor administration in neural cells. Together these data indicate that ERK1/2 and JNK activation may play differential roles in modulating neurochemical disturbances and neurotoxicity induced by proteasome inhibition., ((c) 2009 Wiley-Liss, Inc.)

Many human immunodeficiency virus (HIV) proteins including Tat are produced by HIV-infected astrocytes and secreted into the brain resulting in extensive neuronal damage that contributes to the pathogenesis of HIV dementia. The neuroprotective hormone 17beta-estradiol (E2) is known to negatively regulate the HIV transcriptional promoter in human fetal astrocytes (SVGA cell line) in a Tat-dependent manner. In the present study we extended our investigation in HIV-infected SVGA cells and found a reduction in HIV p24 levels following E2 treatment in comparison to control. Although many E2-mediated events occur through estrogen receptor alpha (ERalpha), we found low levels of ERalpha mRNA and failed to detect ERalpha protein in SVGA cells. Paradoxically, when ERalpha was overexpressed the E2-mediated decrease in Tat transactivation of the promotor was prevented. To determine whether ERalpha expression is altered in the human brain following HIV infection, postmortum hippocampal tissue was obtained from cognitively normal HIV- and HIV+ patients, patients diagnosed with either mild cognitive/motor disorder (MCMD) or HIV-associated dementia (HAD). Immunohistochemistry and quantitative real-time PCR (qRT-PCR) for ERalpha and glial fibrillary acidic protein (GFAP) showed that ERalpha mRNA levels were not significantly different between groups, while GFAP increased in the hippocampus in the HIV+ compared to the HIV- group and was decreased in the MCMD and HAD subgroups compared to HIV+ controls. Notably the ratio of ERalpha-positive reactive astrocytes to total reactive astrocytes increased and significantly correlated with the severity of cognitive impairment following HIV infection. The data suggest that E2 would have the most dramatic effect in reducing HIV transcription early in the disease process when the subpopulation of astrocytes expressing ERalpha is low.

This study was undertaken to investigate the effects of prenatal and postnatal exposure to high fat diet on the brain. Female rats were divided into high fat diet (HFD) and control diet (CD) groups 4 weeks prior to breeding and throughout gestation and lactation. After weaning, male progeny were placed on a chow diet until 8 weeks old, and then segregated into HFD or CD groups. At 20 weeks old, rats were evaluated in the Morris water maze, and markers of oxidative stress and inflammation were documented in the brain. In comparison to rats fed CD, cognitive decline in HFD progeny from HFD dams manifested as a decline in retention, but not acquisition, in the water maze. HFD was also associated with significant increases in 3-nitrotyrosine, inducible nitric oxide synthase, IL-6, and glial markers Iba-1 and GFAP, with the largest increases frequently observed in HFD animals born to HFD dams. Thus, these data collectively suggest that HFD increases oxidative and inflammatory signaling in the brain, and further indicate that maternal HFD consumption might sensitize offspring to the detrimental effects of HFD.

The incidence of obesity is increasing worldwide, and is especially pronounced in developed western countries. While the consequences of obesity on metabolic and cardiovascular physiology are well established, epidemiological and experimental data are beginning to establish that the central nervous system (CNS) may also be detrimentally affected by obesity and obesity-induced metabolic dysfunction. In particular, data show that obesity in human populations is associated with cognitive decline and enhanced vulnerability to brain injury, while experimental studies in animal models confirm a profile of heightened vulnerability and decreased cognitive function. This review will describe findings from human and animal studies to summarize current understanding of how obesity affects the brain. Furthermore, studies aimed at identifying key elements of body-brain dialog will be discussed to assess how various metabolic and adipose-related signals could adversely affect the CNS. Overall, data suggest that obesity-induced alterations in metabolism may significantly synergize with age to impair brain function and accelerate age-related diseases of the nervous system. Thus, enhanced understanding of the effects of obesity and obesity-related metabolic dysfunction on the brain are especially critical as increasing numbers of obese individuals approach advanced age.

A number of metabolic disturbances occur in response to the consumption of a high fat western diet. Such metabolic disturbances can include the progressive development of hyperglycemia, hyperinsulemia, obesity, metabolic syndrome, and diabetes. Cumulatively, diet-induced disturbances in metabolism are known to promote increased morbidity and negatively impact life expectancy through a variety of mechanisms. While the impact of metabolic disturbances on the hepatic, endocrine, and cardiovascular systems is well established there remains a noticeable void in understanding the basis by which the central nervous system (CNS) becomes altered in response to diet-induced metabolic dysfunction. In particular, it remains to be fully elucidated which established features of diet-induced pathogenesis (observed in non-CNS tissues) are recapitulated in the brain, and identification as to whether the observed changes in the brain are a direct or indirect effect of peripheral metabolic disturbances. This review will focus on each of these key issues and identify some critical experimental questions which remain to be elucidated experimentally, as well as provide an outline of our current understanding for how diet-induced alterations in metabolism may impact the brain during aging and age-related diseases of the nervous system.