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Sirtuin 2 (SIRT2) has been proposed to have a central role on aging, inflammation, cancer and neurodegenerative diseases; however, its specific function remains controversial. Recent studies propose SIRT2 pharmacological inhibition as a therapeutic strategy for several neurodegenerative diseases including Alzheimer’s disease (AD). Surprisingly, none of these published studies regarding the potential interest of SIRT2 inhibition has assessed the peripheral adverse side consequences of this treatment. In the present study we demonstrate that pharmacological treatment with 33i improved cognitive dysfunction and LTP, and reduced amyloid pathology and neuroinflammation in the APP/PS1 AD mouse model. However, this treatment increased peripheral levels of inflammatory cytokines IL-1β, Tnf-α, Tgf-β, IL-6 and MCP-1. Accordingly, peripheral SIRT2 inhibition with the blood brain barrier impermeable compound AGK-2, worsened the cognitive capacities and increased systemic inflammation. These results suggest that, although SIRT2 pharmacological inhibition may have beneficial consequences in neurodegenerative diseases, its systemic adverse side effects should be taken into account. This information is essential to maximize the therapeutic potential of SIRT2 inhibition not only for AD but also for other neurodegenerative diseases.

Astrocytes are considered an essential source of blood-borne glucose or its metabolites to neurons. Nonetheless, the necessity of the main astrocyte glucose transporter, i.e. GLUT1, for brain glucose metabolism has not been defined. Unexpectedly, we found that brain glucose metabolism was paradoxically augmented in mice with astrocytic GLUT1 ablation (GLUT11′GFAP mice). These mice also exhibited improved peripheral glucose metabolism especially in obesity, rendering them metabolically healthier. Importantly, GLUT11′GFAP mice did not present cognitive alterations. Mechanistically, we observed that GLUT1-ablated astrocytes exhibited increased insulin receptor-dependent ATP release, and both astrocyte insulin signalling and brain purinergic signalling are essential for improved brain function and systemic glucose metabolism. Collectively, we demonstrate that astrocytic GLUT1 is central to the regulation of brain energetics, yet its ablation triggers a reprogramming of brain metabolism sufficient to sustain energy requirements, peripheral glucose homeostasis and cognitive function.

Alzheimer’s disease (AD) is the main type of dementia and is a disease with a profound socioeconomic burden due to the lack of effective treatment. In addition to genetics and environmental factors, AD is highly associated with metabolic syndrome, defined as the combination of hypertension, hyperlipidemia, obesity and type 2 diabetes mellitus (T2DM). Among these risk factors, the connection between AD and T2DM has been deeply studied. It has been suggested that the mechanism linking both conditions is insulin resistance. Insulin is an important hormone that regulates not only peripheral energy homeostasis but also brain functions, such as cognition. Insulin desensitization, therefore, could impact normal brain function increasing the risk of developing neurodegenerative disorders in later life. Paradoxically, it has been demonstrated that decreased neuronal insulin signalling can also have a protective role in aging and protein-aggregation-associated diseases, as is the case in AD. This controversy is fed by studies focused on neuronal insulin signalling. However, the role of insulin action on other brain cell types, such as astrocytes, is still unexplored. Therefore, it is worthwhile exploring the involvement of the astrocytic insulin receptor in cognition, as well as in the onset and/or development of AD.

Resumen Objetivos La enfermedad de Alzheimer (EA) es una enfermedad neurodegenerativa. La EA es la principal causa de demencia en el mundo, siendo el envejecimiento el principal factor de riesgo. Los criterios diagnósticos para la enfermedad de Alzheimer suelen basarse en datos clínicos. No obstante, es necesario establecer una definición biológica de la enfermedad de Alzheimer basada en biomarcadores que reflejen la neuropatología subyacente. Contenido El objetivo de esta revisión es presentar los resultados obtenidos en la medición de biomarcadores nuevos y ya conocidos en los fluidos biológicos o en neuroimágenes. Resumen Actualmente se emplean tres biomarcadores para el diagnóstico de la enfermedad de Alzheimer_Aβ42, t-Tau y p-Tau. El uso diagnóstico de biomarcadores en el líquido cefalorraquídeo (LCR) presenta algunas limitaciones debido a que la obtención invasiva mediante punción lumbar puede provocar efectos secundarios. La práctica más común en los centros clínicos es la medición en plasma o suero, ya que es mínimamente invasiva y, en consecuencia, se puede obtener y procesar con mayor facilidad. Las dos principales proteínas implicadas en el proceso patológico, Aβ y Tau, se pueden visualizar empleando técnicas de neuroimagen como la PET. Perspectivas Dado que está ampliamente aceptado que la enfermedad de Alzheimer comienza décadas antes de que se diagnostiquen los primeros síntomas clínicos, la detección de alteraciones biológicas previa a la aparición de la sintomatología clínica permitiría su diagnóstico precoz o incluso abriría la puerta a nuevas opciones terapéuticas.

Background Alzheimer’s disease (AD) is a progressive neurodegenerative disease. AD is the main cause of dementia worldwide and aging is the main risk factor for developing the illness. AD classical diagnostic criteria rely on clinical data. However, the development of a biological definition of AD using biomarkers that reflect the underling neuropathology is needed. Content The aim of this review is to describe the main outcomes when measuring classical and novel biomarkers in biological fluids or neuroimaging. Summary Nowadays, there are three classical biomarkers for the diagnosis of AD: Aβ42, t-Tau and p-Tau. The diagnostic use of cerebrospinal fluid biomarkers is limited due to invasive collection by lumbar puncture with potential side effects. Plasma/serum measurements are the gold standard in clinics, because they are minimally invasive and, in consequence, easily collected and processed. The two main proteins implicated in the pathological process, Aβ and Tau, can be visualized using neuroimaging techniques, such as positron emission tomography. Outlook As it is currently accepted that AD starts decades before clinical symptoms could be diagnosed, the opportunity to detect biological alterations prior to clinical symptoms would allow early diagnosis or even perhaps change treatment possibilities.

c-Jun N-terminal kinases (JNKs) are a family of protein kinases that can be activated by numerous stimuli and regulate a broad spectrum of biological processes in the Central Nervous System. JNK3, a specific isoform in the brain, have been shown to be involved in neurodegenerative conditions. Even though JNK over-activation has been observed in human brains affected with Alzheimer’s disease (AD), its role in AD pathology development is still unclear. One of the early regions of neuronal volume loss in AD is the Entorhinal Cortex (EC). Indeed, the loss of projections from EC to hippocampus (Hp) in the early phases of AD has raised the idea that the connection between EC and Hp could be deteriorated in AD. Thus, the main aim of the current work is to address if JNK3 overexpression in the EC could spread to the hippocampus, leading to cognitive deficiencies, similar to what occurs in early stages of AD. Data acquired in the current study suggest that JNK3 overexpression in the EC is also observed in the Hp and this leads to cognitive impairment. Moreover, pro-inflammatory cytokines expression and Tau immunoreactivity appeared to be increased both in the EC and Hp. Therefore, activation of inflammatory signaling and induction of Tau aberrant misfolding caused by JNK3 could be the underlying mechanism of the observed cognitive impairment. Altogether, JNK3 overexpression may disseminate from EC to Hp inducing cognitive dysfunction in vulnerable brain regions and may underlie the alterations observed in early stages of AD.

It has been established that ageing is the major risk factor for cognitive deficiency and it is becoming increasingly evident that insulin resistance is another factor. Biological plausibility for a link between insulin resistance and dementia is relevant for understanding disease etiology, and to form bases for prevention efforts to decrease disease burden. In the present study, peripheral and central insulin resistance was found in SAMP8 mice (aging mouse model) accompanied by cognitive deficiencies. Furthermore, a marked peripheral inflammatory state was observed in SAMP8 mice, followed by neuroinflammation that could be due to a higher cytokine leaking into the brain across an aging-disrupted blood brain barrier. Moreover, aging-induced gut dysbiosis produces higher TMAO that could also contribute to the peripheral and central inflammatory tone as well as to the cognitive deficiencies observed in SAMP8 mice. All those alterations were reversed by DMB, a treatment that decreases TMAO levels. Data obtained from this project suggest that microbial dysbiosis and increased TMAO secretion could be a key link between aging, insulin resistance and dementia. Thus, pharmacological intervention that leads to decreased TMAO levels, such as DMB, could open a new avenue for the future treatment of neurodegenerative diseases.

It has been established that ageing is the major risk factor for cognitive deficiency or neurodegenerative diseases such as Alzheimer’s disease (AD) and it is becoming increasingly evident that insulin resistance is another factor. Biological plausibility for a link between insulin resistance and dementia is relevant for understanding disease etiology, and to form bases for prevention efforts to decrease disease burden.The dysfunction of the insulin signaling system and glucose metabolism has been proposed to be responsible for brain aging. Normal insulin signaling in the brain is required to mediate growth, metabolic functions, and the survival of neurons and glia. Insulin receptors are densely expressed in the olfactory bulb, the cerebral cortex and the hippocampus and regulate neurotransmitter release and receptor recruitment. In normal elderly individuals, reduced glucose tolerance and decreased insulin levels in the aged brain are typically observed. Furthermore, insulin signaling is aberrantly activated in the AD brain, leading to non-responsive insulin receptor signaling.The senescence accelerated mouse (SAMP8) mouse was one of the accelerated senescence strains that spontaneously developed from breeding pairs of the AKR/J series. The SAMP8 mouse develops early learning and memory deficits (between 6 and 8 months) together with other characteristics similar to those seen in Alzheimer’s disease. The present project proposes the investigation of the missing link between aging, insulin resistance and dementia.Peripheral but not central insulin resistance was found in SAMP8 mice accompanied by cognitive deficiencies. Furthermore, a marked peripheral inflammatory state (i.e. significantly higher adipose tissue TNF-α and IL6 levels) were observed in SAMP8 mice, followed by neuroinflammation that could be due to a higher cytokine leaking into the brain across a aging-disrupted BBB. Moreover, aging-induced gut dysbiosis produces higher TMAO that could also contribute to the peripheral and central inflammatory tone as well as to the cognitive deficiencies observed in SAMP8 mice. All those alterations were reversed by DMB, a treatment inhibits the transformation of choline, carnitine and crotonobetaine, decreaseing TMAO levels.The ever-increasing incidence of neurodegenerative diseases not only limits the life quality of the affected individuals and their families but also poses an enormous demand on the societies. Thus, it is instrumental to pursue novel promising approaches to prevent and treat it at the highest possible speed to rapidly translate them to clinical practice. From this point of view, data obtained from this project will be instrumental to validate the principle approach of microbial dysbiosis and increased TMAO secretion as a key link between aging, insulin resistance and dementia. Collectively, the proposed experiments ideally integrate the aim to promote a novel approach to improve the lives of those suffering from cognitive disturbances.

Even though the involvement of serotonin (5-hydroxytryptamine; 5-HT) and its receptors in Alzheimer's disease (AD) is widely accepted, data on the expression and the role of 5-HT7 receptors in AD is relatively limited. Therefore, the objective of the present work was to study the expression of serotonergic 5-HT7 receptors in postmortem samples of AD brains and correlate it with neurotransmitter levels, cognition and behavior. The study population consisted of clinically well-characterized and neuropathologically confirmed AD patients (n = 42) and age-matched control subjects (n = 18). Reverse-transcription quantitative polymerase chain reaction (RT-qPCR) and high-performance liquid chromatography were performed on Brodmann area (BA) 7, BA10, BA22, BA24, hippocampus, amygdala, thalamus and cerebellum to measure mRNA levels of 5-HT7 receptors (HTR7), as well as the concentrations of various monoamine neurotransmitters and their metabolites.Decreased levels of HTR7 mRNA were observed in BA10. A significant association was observed between HTR7 levels in BA10 and BEHAVE-AD cluster B (hallucinations) (rs(28) = 0.444, P < 0.05). In addition, a negative correlation was observed between HTR7 levels in BA10 and both MHPG concentrations in this brain region (rs(45) = -0.311; P < 0.05), and DOPAC levels in the amygdala (rs(42) = -0.311; P < 0.05). Quite surprisingly, no association was found between HTR7 levels and cognitive status. Altogether, this study supports the notion of the involvement of 5-HT7 receptors in psychotic symptoms in AD, suggesting the interest of testing antagonist acting at this receptor to specifically treat psychotic symptoms in this illness.

Even though the involvement of serotonin (5-hydroxytryptamine; 5-HT) and its receptors in Alzheimer's disease (AD) is widely accepted, data on the expression and the role of 5-HT

Blood-Brain barrier (BBB) disruption is a hallmark of central nervous system (CNS) dysfunction, and oxidative stress is one of the molecular mechanisms that may underlie this process. NADPH oxidases (NOX) are involved in oxidative stress-mediated vascular dysfunction and participate in the pathophysiology of its target organs. The NADPH oxidase 5 (NOX5) isoform is absent in rodents, and although little is known about the role it may play in disrupting the BBB, it has recently been implicated in experimental stroke. Our aim was to investigate the role of NADPH oxidase 5 (NOX5) in promoting vascular alterations and to identify its impact on the cognitive status of aged mice. No differences were detected in the arterial blood pressure or body weight between knock-in mice expressing endothelial NOX5 and the control mice. The Morris water maze test showed memory impairments in the aged knock-in mice expressing NOX5 compared with their control littermates. For assessing the BBB integrity, we studied the protein expression of two tight junction (TJ) proteins: Zonula occludens-1 (ZO-1) and occludin. Compared to the control animals, Aged NOX5 mice exhibited reduced levels of both proteins, demonstrating an alteration of the BBB integrity. Our data indicate that vascular NOX5 may favor behavioral changes with aging through oxidative stress-mediated BBB breakdown.

Recent investigations have increased the interest on the connection between the microorganisms inhabiting the gut (gut microbiota) and human health. An imbalance of the intestinal bacteria representation (dysbiosis) could lead to different diseases, ranging from obesity and diabetes, to neurological disorders including Alzheimer's disease (AD). The term "gut-brain axis" refers to a crosstalk between the brain and the gut involving multiple overlapping pathways, including the autonomic, neuroendocrine, and immune systems as well as bacterial metabolites and neuromodulatory molecules. Through this pathway, microbiota can influence the onset and progression of neuropathologies such as AD. This review discusses the possible interaction between the gut microbiome and AD, focusing on the role of gut microbiota in neuroinflammation, cerebrovascular degeneration and Aβ clearance.

A potential role of marine n-3 polyunsaturated fatty acids (ω-3 PUFAs) has been suggested in memory, learning, and cognitive processes. Therefore, ω-3 PUFAs might be a promising treatment option, albeit controversial, for Alzheimer's disease (AD). Among the different mechanisms that have been proposed as responsible for the beneficial effects of ω-3 PUFAs, inhibition of JNK stands as a particularly interesting candidate. In the present work, it has been studied whether the administration of two different PUFAs (docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA)) and a DHA-derived specialized pro-resolving lipid mediator (MaR1) is able to reverse cognitive deficits in the senescence-accelerated mouse prone 8 (SAMP8) mouse model of sporadic AD. The novel object recognition test (NORT) test showed that recognition memory was significantly impaired in SAMP8 mice, as shown by a significantly decreased discrimination index that was reversed by MaR1 and DHA. In the retention phase of the Morris water maze (MWM) task, SAMP8 mice showed memory deficit that only DHA treatment was able to reverse. pJNK levels were significantly increased in the hippocampus of SAMP8 mice compared to SAMR1 mice, and only DHA treatment was able to significantly reverse these increased pJNK levels. Similar results were found when measuring c-Jun, the main JNK substrate. Consequently to the increases in tau phosphorylation after increased pJNK, it was checked that tau phosphorylation (PHF-1) was increased in SAMP mice, and this effect was reversed after DHA treatment. Altogether, DHA could represent a new approach for the treatment of AD through JNK inhibition.

Nimodipine may be of interest to treat behavioral alterations and memory deficits. However, its oral administration is hampered by a low bioavailability. The aim of this work was to develop pegylated nanoparticles as oral carriers of nimodipine and test their capability to both reverse the anxiety and protect against cognitive impairment of in stressed mice. Pegylated nanoparticles (NMD-NP/PEG), with a size of 190 nm and a payload of 68 µg/mg, significantly improve the oral bioavailability of nimodipine; about 7-times higher than for the control drug solution (62% vs 9%). The effect of oral nimodipine on the anxiety and cognitive capabilities in a model of stressed mice was also evaluated. NMD-NP/PEG displayed a poor effect on the anxiety-like behavior of animals. Nevertheless, only the treatment with NMD-NP/PEG exerted a protective effect against the memory impairments induced by chronic corticosterone administration, improving the cognitive capabilities of animals when compared with controls. These pegylated nanocarriers may represent a useful strategy to develop new oral treatments for preventing from cognitive impairments.

Obesity prevalence is increasing steadily throughout the world's population in most countries and in parallel the prevalence of metabolic disorders including cardiovascular diseases and type 2 diabetes is also rising, but less is reported about excessive adiposity relationship with poorer cognitive performance, cognitive decline and dementia. Some human clinical studies have evidenced that obesity is related to the risk of the development of mild cognitive impairment, in the form of short-term memory and executive function deficits, as well as dementia and Alzheimer's disease. The precise mechanisms that underlie the connections between obesity and the risk of cognitive impairment are still largely unknown but potential avenues of further research include insulin resistance, the gut-brain axis, and systemic mediators and central inflammation processes. A common feature of metabolic diseases is a chronic and low-grade activation of the inflammatory system. This inflammation may eventually spread from peripheral tissue to the brain, and recent reports suggest that neuroinflammation is an important causal mechanism in cognitive decline. This inflammatory status could be triggered by changes in the gut microbiota composition. Consumption of diets high in fat and sugar influences the microbiota composition, which may lead to an imbalanced microbial population in the gut. Thus, it has recently been hypothesized that the gut microbiota could be part of a mechanistic link between the consumption of high fat and other unbalanced diets and impaired cognition, termed 'gut-brain axis'. The present review will aim at providing an integrative analysis of the effects of obesity and unbalanced diets on cognitive performance and discusses some of the potential mechanisms involved, namely inflammation and changes in gut-brain axis. Moreover, the review aims to analyze anti-inflammatory drugs that have been tested for the treatment of cognition and obesity, recently approved anti-obesity drugs that could also have an impact on central nervous system, and bioactive food compounds that modulate gut microbiota and could have an impact through the gut-brain axis. In this era of precision nutrition medicine, it is imperative to identify the various metabolic-neurocognitive phenotypes in order to understand the processes that drive these diseases so that targeted therapeutic strategies to prevent and successfully manage these complex, multifactorial diseases could be designed and developed.

Alzheimer's disease (AD) is the most common cause of dementia in elderly people. Because of the lack of effective treatments for this illness, research focused on identifying compounds that restore cognition and functional impairments in patients with AD is a very active field. Since its discovery in 1993, the serotonin 5-HT6 receptor has received increasing attention, and a growing number of studies supported 5-HT6 receptor antagonism as a target for improving cognitive dysfunction in AD. This article reviews the rationale behind investigations into the targeting of 5-HT6 receptors as a symptomatic treatment for cognitive and/or behavioral symptoms of AD. In addition to describing the available clinical evidence, this article also describes the purported biochemical and neurochemical mechanisms of action by which 5-HT6 receptor antagonists could influence cognition, and the preclinical data supporting this therapeutic approach to AD. A large number of publications describing the development of ligands for this receptor have come to light and preclinical data indicate the procognitive efficacy of 5-HT6 receptor antagonists. Subsequently, the number of patents protecting 5-HT6 chemical entities has continuously grown. Some of these compounds have successfully undergone phase I clinical studies and have been further evaluated in clinical phase II trials with variable success. Phase II studies have also revealed the potential of combining 5-HT6 receptor antagonism and cholinesterase inhibition. Two of these antagonists, idalopirdine and RVT-101, have been further developed into ongoing phase III clinical trials. Overall, 5-HT6 receptor antagonists can reasonably be regarded as potential drug candidates for the treatment of AD.

The brain depends on glucose as a source of energy. This implies the presence of glucose transporters, being GLUT1 and GLUT3 the most relevant. Expression of GLUT12 is found in mouse and human brain at low levels. We previously demonstrated GLUT12 upregulation in the frontal cortex of aged subjects that was even higher in aged Alzheimer's disease (AD) patients. However, the cause and the mechanism through which this increase occurs are still unknown. Here, we aimed to investigate whether the upregulation of GLUT12 in AD is related with aging or Aβ deposition in comparison with GLUT1, GLUT3, and GLUT4. In the frontal cortex of two amyloidogenic mouse models (Tg2576 and APP/PS1) GLUT12 levels were increased. Contrary, expression of GLUT1 and GLUT3 were decreased, while GLUT4 did not change. In aged mice and the senescence-accelerated model SAMP8, GLUT12 and GLUT4 were upregulated in comparison with young animals. GLUT1 and GLUT3 did not show significant changes with age. The effect of β-amyloid (Aβ) deposition was also evaluated in Aβ peptide i.c.v. injected mice. In the hippocampus, GLUT12 expression increased whereas GLUT4 was not modified. Consistent with the results in the amyloidogenic models, GLUT3 and GLUT1 were downregulated. In summary, Aβ increases GLUT12 protein expression in the brain pointing out a central role of the transporter in AD pathology and opening new perspectives for the treatment of this neurodegenerative disease.

Five pharmaceutical strategies are currently approved by the US FDA for the treatment of obesity: orlistat, lorcaserin, liraglutide, phentermine/topiramate, and bupropion/naltrexone. The most effective treatment seems to be the combined administration of phentermine/topiramate followed by lorcaserin and bupropion/naltrexone. In relation to the management of excessive weight, other aspects also need to be considered, including comorbidities accompanying obesity, drug interactions, and the risk of negative collateral effects, as well as individualized treatments based on the genetic make-up. This review aims to provide an overview of the approved anti-obesity drugs and newer molecules that could affect different targets in the central nervous system or peripheral tissues, the molecular mechanisms, emerging dietary treatments and phytogenic compounds, and pharmacogenetic/nutrigenetic approaches for personalized obesity management.

Alzheimer's disease (AD) is characterized phenotypically by memory impairment, histologically by accumulation of pTau and β-amyloid peptide and morphologically by a loss of nerve terminals in cortical and hippocampal regions. As glutamate is the principle excitatory neurotransmitter of the central nervous system (CNS), the glutamatergic system may play an important role in AD. To date, not many studies have addressed the deleterious effects of Aβ on glutamatergic terminals; therefore the aim of this study was to investigate how Aβ affects glutamatergic terminals and to assess the extent to which alterations in the glutamatergic neurotransmission could impact susceptibility to the illness. The present study shows that Aβ caused a loss of glutamatergic terminals, measured by VGLUT1 protein levels, in Tg2576 primary cell cultures, Tg2576 mice and AD patient brains, and also when Aβ was added exogenously to hippocampal cell cultures. Interestingly, no correlation was found between cognition and decreased VGLUT1 levels. Moreover, when Aβ1-42 was intracerebroventricularlly administered into VGLUT1+/- mice, altered synaptic plasticity and increased neuroinflammation was observed in the hippocampus of those animals. In conclusion, the present study not only revealed susceptibility of glutamatergic nerve terminals to Aβ induced toxicity but also underlined the importance of VGLUT1 in the progression of AD, as the decrease of this protein levels could increase the susceptibility to subsequent deleterious inputs by exacerbating Aβ induced neuroinflammation and synaptic plasticity disruption. © 2016 Wiley Periodicals, Inc.

High-fat diet (HFD) feeding induces rapid reprogramming of systemic metabolism. Here, we demonstrate that HFD feeding of mice downregulates glucose transporter (GLUT)-1 expression in blood-brain barrier (BBB) vascular endothelial cells (BECs) and reduces brain glucose uptake. Upon prolonged HFD feeding, GLUT1 expression is restored, which is paralleled by increased expression of vascular endothelial growth factor (VEGF) in macrophages at the BBB. In turn, inducible reduction of GLUT1 expression specifically in BECs reduces brain glucose uptake and increases VEGF serum concentrations in lean mice. Conversely, myeloid-cell-specific deletion of VEGF in VEGF(Δmyel) mice impairs BBB-GLUT1 expression, brain glucose uptake, and memory formation in obese, but not inlean mice. Moreover, obese VEGF(Δmyel) mice exhibit exaggerated progression of cognitive decline and neuroinflammation on an Alzheimer's disease background. These experiments reveal that transient, HFD-elicited reduction of brain glucose uptake initiates a compensatory increase of VEGF production and assign obesity-associatedmacrophage activation a homeostatic role torestore cerebral glucose metabolism, preserve cognitive function, and limit neurodegeneration in obesity.

Trimethylamine N-oxide (TMAO) is a molecule generated from choline, betaine, and carnitine via gut microbial metabolism. The plasma level of TMAO is determined by several factors including diet, gut microbial flora, drug administration and liver flavin monooxygenase activity. In humans, recent clinical studies evidence a positive correlation between elevated plasma levels of TMAO and an increased risk for major adverse cardiovascular events. A direct correlation between increased TMAO levels and neurological disorders has been also hypothesized. Several therapeutic strategies are being explored to reduce TMAO levels, including use of oral broad spectrum antibiotics, promoting the growth of bacteria that use TMAO as substrate and the development of target-specific molecules. Despite the accumulating evidence, it is questioned whether TMAO is the mediator of a bystander in the disease process. Thus, it is important to undertake studies to establish the role of TMAO in human health and disease. In this article, we reviewed dietary sources and metabolic pathways of TMAO, as well as screened the studies suggesting possible involvement of TMAO in the etiology of cardiovascular and neurological disorders, underlying the importance of TMAO mediating inflammatory processes. Finally, the potential utility of TMAO as therapeutic target is also analyzed.

Tau is a microtubule-associated protein highly expressed in neurons with a chief role in microtubule dynamics and axonal maintenance. Adrenomedullin gene (ADM) codifies for various peptides that exert broad range of actions in the body. Previous works in our groups have shown that increased ADM products are positively correlated to microtubule disruption and tau pathology in Alzheimer’s disease brains. In the present study, we explore the involvement of ADM in the neuropathology of frontotemporal lobar degeneration that presents with primary tauopathy (FTLD-tau). Proteins from frontal cortices of FTLD-tau patients and age- and sex-matched non-demented controls were analyzed with antibodies against different microtubule components, including adrenomedullin, and synaptic markers. Tau pathology in frontal cortex from FTLD patients was confirmed. Levels of total βIII-tubulin as well as acetylated and detyrosinated tubulins, two markers of stabilized and aged microtubules, were significantly reduced and directly correlated with PSD95 and proBDNF in FTLD-tau patients when compared to non-demented controls. In contrast, no change in actin cytoskeleton was found. Interestingly, changes in microtubule elements, indicators of disturbed axonal preservation, were accompanied by decreased levels of free adrenomedullin, although no association was found. Altogether, reduced levels of adrenomedullin might not be directly linked to the microtubule pathology of FTLD-tau, but based on previous works, it is suggested that downregulation of ADM might be an adaptive attempt of neurons to mitigate microtubule disruption.

Alzheimer’s disease (AD) is the most common cause of dementia in elderly people. The current lack of effective treatments for the illness demands a deep knowledge of the processes underlying normal and pathological brain aging. Diet-induced obesity, inflammation, and insulin resistance have been recognized as important players in the pathogenesis of AD. The classic view of insulin as principal regulator of glucose homeostasis has been expanded to a large range of effects, including the regulation of learning and memory. Several studies have raised the possibility that systemic insulin resistance and AD share similar molecular roots. In this review we focus on describing the mechanisms by which a high-fat diet and/or obesity can impair systemic and brain insulin signaling and cognition. Moreover, some nutritional interventions that may help to attenuate diet-induced cognitive decline, including the omega-3 fatty acid supplementation or the role of α-lipoic acid, are summarized.

It is believed that glucocorticoids control the proliferation of neural progenitor cells, and this process is highly involved in mood disorders and cognitive processes. Using the maternal separation model of chronic neonatal stress, it has been found that stress induced depressive-like behavior, cognitive deficits and a decrease in proliferation in the subventricular zone (SVZ). Venlafaxine reversed all deleterious effects of chronic stress by modulating HPA activity. These outcomes suggest modulation of stress-mediated glucocorticoid secretion as a target for the treatment of mood disorders and neurodegenerative processes.

Alzheimer’s disease (AD) is characterized by the loss of synaptic contacts caused in part by cytoskeleton disruption. Adrenomedullin (AM) is involved in physiological functions such as vasodilation, hormone secretion, antimicrobial activity, cellular growth, and angiogenesis. In neurons, AM and related peptides are associated with some structural and functional cytoskeletal proteins, causing microtubule destabilization. Here, we describe the relationships between AM and other signs of AD in clinical specimens. Frontal cortex from AD patients and controls were studied for AM, acetylated tubulin, NCAM, Ox-42, and neurotransmitters. AM was increased in AD compared with controls, while levels of acetylated tubulin, NCAM, and neurotransmitters were decreased. Interestingly, increases in AM statistically correlated with the decrease in these markers. Furthermore, Ox42 overexpression in AD correlated with levels of AM. It is proposed that AD patients may have neural cytoskeleton failure associated with increase of AM levels, resulting in axon transport collapse and synaptic loss. These observations suggest that reducing AM expression may constitute a new avenue to prevent/treat AD.

Alzheimer's disease (AD) is the most common cause of dementia in elderly people. Because of the lack of effective treatments for this illness, research focused on identifying compounds that restore cognition and functional impairments in patients with AD is a very active field. Since its discovery in 1993, the serotonin 5-HT

It is becoming evident that chronic exposure to stress not only might result in insulin resistance or cognitive deficits, but may also be considered a risk factor for pathologies such as depression or Alzheimer's disease (AD). There is great interest in determining the molecular mechanisms underlying interactions between stress, aging, memory and Alzheimer's disease (AD). We have used the chronic mild stress (CMS) model to study the effects of chronic stress on the aging process and the development of central insulin resistance and AD pathology. CMS aged mice showed cognitive impairments in the novel object recognition test. In addition, CMS aged mice displayed both peripheral insulin resistance, as shown by HOMA index, and decreased hippocampal levels of pIRS and downstream intracellular signaling (pAKT, pGSK and pERK1/2). Interestingly, there was a significant increase in both C99:C83 ratio and BACE1 levels in the hippocampus of CMS aged mice. Increased expression of the AD marker pTau was also found in stressed aged mice. Increased expression of the stress-activated protein kinase JNK was found in CMS aged mice, accompanied by significant decreases in glucocorticoid receptor (GR) expression and increases in mineralocorticoid receptor (MR) expression. It is suggested that the interaction of stress with aging should be considered when studying determinants of the onset and progression of AD.

The cannabinoid system seems to play an important role in various neurodegenerative diseases including Alzheimer's disease (AD). The relationship of cannabinoid receptors (CB(1)R and CB(2)R) to cognitive function and neuropathological markers in AD remains unclear. In the present study, postmortem cortical brain tissues (Brodmann area 10) from a cohort of neuropathologically confirmed AD patients and age-matched controls were used to measure CB(1)R and CB(2)R by immunoblotting. Correlational analyses were performed for the neurochemical and cognitive data. CB(1)R expression was significantly decreased in AD. Levels of CB(1)R correlated with hypophagia, but not with any AD molecular marker or cognitive status (Mini Mental State Examination score). The level of CB(2)R was significantly higher (40%) in AD. Increases in the expression of the glial marker glial fibrillar acidic protein were also found. CB(2)R expression did not correlate with cognitive status. Interestingly, expression levels of CB(2)R correlated with two relevant AD molecular markers, Aβ(42) levels and senile plaque score. These results may constitute the basis of CB(2)R-based therapies and/or diagnostic approaches.

In the present work, the involvement of JNK in insulin signaling alterations and its role in glutamatergic deficits in Alzheimer's disease (AD) has been studied. In postmortem cortical tissues, pJNK levels were increased, while insulin signaling and the expression of VGLUT1 were decreased. A significant correlation was found between reduced expression of insulin receptor and VGLUT1. The administration of a JNK inhibitor reversed the decrease in VGLUT1 expression found in a mice model of insulin resistance. It is suggested that activation of JNK in AD inhibits insulin signaling which could lead to a decreased expression of VGLUT1, therefore contributing to the glutamatergic deficit in AD.

c-Jun N-terminal kinases (JNKs) are a family of protein kinases that play a central role in stress signaling pathways implicated in gene expression, neuronal plasticity, regeneration, cell death and regulation of cellular senescence. It has been shown that there is a JNK pathway activation after exposure to different stressing factors, including cytokines, growth factors, oxidative stress, unfolded protein response signals or A peptides. Altogether, JNKs have become a focus of screening strategies searching for new therapeutic approaches to diabetes, cancer or liver diseases. In addition, activation of JNK has been identified as a key element responsible for the regulation of apoptotic apoptosis signals and therefore, it is critical for pathological occurring cell death associated with neurodegenerative diseases and, among them, with Alzheimer's disease (AD). In addition, in vitro and in vivo studies have reported alterations of JNK pathways potentially associated with pathogenesis and neuronal death in AD. JNK’s, particularly JNK3, not only enhance Aβ production, moreover it plays a key role in the maturation and development of neurofibrillary tangles. This review aims to explain the rationale behind testing therapies based on inhibition of JNK signalling for AD in terms of current knowledge about the pathophysiology of the disease. Keeping in mind that JNK3 is specifically expressed in the brain and activated by stress-stimuli, it is possible to hypothesize that inhibition of JNK3 might be considered as a potential target for treating neurodegenerative mechanisms associated with AD.

The objective of the present work was to study the effects of an early-life stress (maternal separation, MS) in the excitatory/inhibitory ratio as a potential factor contributing to the ageing process, and the purported normalizing effects of chronic treatment with the antidepressant venlafaxine. MS induced depressive-like behaviour in the Porsolt forced swimming test that was reversed by venlafaxine, and that persisted until senescence. Aged MS rats showed a downregulation of vesicular glutamate transporter 1 and 2 (VGlut1 and VGlut2) and GABA transporter (VGAT) and increased expression of excitatory amino acid transporter 2 (EAAT2) in the hippocampus. Aged rats showed decreased expression of glutamic acid decarboxylase 65 (GAD65), while the excitatory amino acid transporter 1 (EAAT1) was affected only by stress. Glutamate receptor subunits NR1 and NR2A and GluR4 were upregulated in stressed rats, and this effect was reversed by venlafaxine. NR2B, GluR1 and GluR2/3 were not affected by either stress or age. MS, both in young and aged rats, induced an increase in the circulating levels of corticosterone. Corticosterone induced an increase glutamate and a decrease in GABA release in hippocampal slices, which was reversed by venlafaxine. Chronic treatment with corticosterone recapitulated the main biochemical findings observed in MS. The different effects that chronic stress exerts in young and adult animals on expression of proteins responsible for glutamate/GABA cycling may explain the involvement of glucocorticoids in ageing-related diseases. Modulation of glutamate/GABA release may be a relevant component of the therapeutic action of antidepressants, such as venlafaxine.

BACKGROUND AND PURPOSE Stress is believed to be associated with the development of neuropsychiatric disorders, including Alzheimer's disease (AD). We have studied mechanisms implicated in vulnerability to stress and the relationship with changes in AD-related markers. EXPERIMENTAL APPROACH Anhedonia induced by a chronic mild stress (CMS) procedure, applied for 6 weeks, was used to select rats vulnerable or resistant to stress. Sucrose intake, the Porsolt forced swimming test and cognitive deficits in the novel object recognition test (NORT) were used to characterize vulnerable and resilient rats. The antidepressant venlafaxine (20 mg·kg−1 p.o.) or saline was administered daily during the last 2 weeks of CMS. Biochemical markers affected by stress, PKB, ERK and synaptophysin, and those associated with AD, amyloid β-protein (Aβ), β-secretase (BACE1) and τ phosphorylation, were measured in the hippocampus. KEY RESULTS After CMS, 40% of rats were resistant to the development of anhedonia (CMS-resistant to stress), whereas the remaining were responsive [CMS-anhedonic (CMSA)]. Only CMSA rats displayed significant increases in immobility time in the forced swimming test and cognitive deficits in the NORT, and significant decreases in synaptophysin, phosphorylated PKB and phosphorylated ERK1/2 expression in the hippocampus. Increased levels of Aβ40, BACE1 and τ phosphorylation were also found only in CMSA rats. All these effects in CMSA rats were reverted by treatment with venlafaxine. CONCLUSIONS AND IMPLICATIONS Vulnerability to stress might constitute a risk factor for the development of AD, and pharmacological treatment with venlafaxine may represent a therapeutic strategy for the treatment of stress-related disorders, including AD.

The World Health Organization has called obesity a global epidemic. There is a strong association between body weight gain and blood pressure. A major determinant of blood pressure is the level of activity in sympathetic nerves innervating cardiovascular organs. A characteristic of obesity, in both humans and in animal models, is an increase in sympathetic nerve activity to the skeletal muscle vasculature and to the kidneys. Obesity is now recognized as a chronic, low level inflammatory condition, and pro-inflammatory cytokines are elevated including those produced by adipose tissue. The most well-known adipokine released from fat tissue is leptin. The adipokine, resistin, is also released from adipose tissue. Resistin can act in the central nervous system to influence the sympathetic nerve activity. Here, we review the effects of resistin on sympathetic nerve activity and compare them with leptin. We build an argument that resistin and leptin may have complex interactions. Firstly, they may augment each other as both are excitatory on sympathetic nerves innervating cardiovascular organs; In contrast, they could antagonize each other's actions on brown adipose tissue, a key metabolic organ. These interactions may be important in conditions in which leptin and resistin are elevated, such as in obesity.

The present work investigated the involvement of cortisol and its receptors, glucocorticoid receptor (GR) and mineralocorticoid receptor (MR), in Alzheimer's disease (AD). Cortisol was measured in cerebrospinal fluid (CSF) samples from controls, mild cognitive impairment (MCI), progressive MCI evolving to AD, and AD. CSF cortisol levels do not seem to have a prognostic value, as increases in cortisol levels were found only in AD patients. GR expression was decreased while MR expression was increased in the frontal cortex of AD. When considering degeneration (ratio to synaptophysin and the post-synaptic marker PSD95), GR expression was similar between controls and AD, suggesting that GR loss was due to synaptic degeneration in AD. Increases in cortisol levels and MR expression were associated to an apolipoprotein E4 genotype. Cognitive status was negatively associated to CSF cortisol. In apolipoprotein E4 carriers, MR but not GR expression, negatively correlated to Mini-Mental Status Examination score and positively correlated to frontal cortex amyloid-β levels. It is concluded that there is a dysregulation of the hypothalamus-pituitary-adrenal axis in AD that seems to be consequence rather than cause of AD.