ABA Supplementation Rescues IRS2 and BDNF mRNA Levels in a Triple-Transgenic Mice Model of Alzheimer's Disease.

Insulin resistance underlies Alzheimer's disease (AD) by affecting neuroinflammation and brain-derived neurotrophic factor (BDNF) expression. Here, we evaluated the effect of early and late-start abscisic acid (ABA) intervention on hippocampal BDNF, tumor necrosis factor α (TNFα), and insulin receptors substrates (IRS) 1/2 mRNA levels in a triple-transgenic mice model of AD. Transgenic mice displayed lower BDNF and IRS2, equal IRS1, and higher TNFα expression compared to wild-type mice. Late ABA treatment could rescue TNFα and increased IRS1/2 expression. However, early ABA administration was required to increase BDNF expression. Our data suggests that early intervention with ABA can prevent AD, via rescuing IRS1/2 and BDNF expression.

Targeting Neuroinflammation with Abscisic Acid Reduces Pain Sensitivity in Females and Hyperactivity in Males of an ADHD Mice Model.

Attention deficit/hyperactivity disorder (ADHD) is a neurodevelopmental syndrome characterized by dopaminergic dysfunction. In this study, we aimed to demonstrate that there is a link between dopaminergic deficit and neuroinflammation that underlies ADHD symptoms. We used a validated ADHD mice model involving perinatal 6-OHDA lesions. The animals received abscisic acid (ABA), an anti-inflammatory phytohormone, at a concentration of 20 mg/L (drinking water) for one month. We tested a battery of behavior tests, learning and memory, anxiety, social interactions, and pain thresholds in female and male mice (control and lesioned, with or without ABA treatment). Postmortem, we analyzed microglia morphology and Ape1 expression in specific brain areas related to the descending pain inhibitory pathway. In females, the dopaminergic deficit increased pain sensitivity but not hyperactivity. In contrast, males displayed hyperactivity but showed no increased pain sensitivity. In females, pain sensitivity was associated with inflammatory microglia and lower Ape1 levels in the anterior cingulate cortex (ACC) and posterior insula cortex (IC). In addition, ABA treatment alleviated pain sensitivity concomitant with reduced inflammation and normalized APE1. In males, ABA reduced hyperactivity but had no significant effect on inflammation in these areas. This is the first study proving a sex-dependent association between dopamine dysfunction and inflammation in specific brain areas, hence leading to different behavioral outcomes in a mouse model of ADHD. These findings provide new clues for potential treatments for ADHD.

Accelerated Polyethylene Terephthalate (PET) Enzymatic Degradation by Room Temperature Alkali Pre-treatment for Reduced Polymer Crystallinity.

Polyethylene terephthalate (PET) is the most widely employed plastic for single-use applications. The use of enzymes isolated from microorganisms, such as PETase with the capacity to hydrolyze PET into its monomers, represents a promising method for its sustainable recycling. However, the accessibility of the enzyme to the hydrolysable bonds is an important challenge that needs to be addressed for effective biodegradation of postconsumer PET. Here, we combined an alkali pre-treatment (25 °C) with PETase incubation (30 °C) with post-consumed PET bottles. The pre-treatment modifies the surface of the plastic and decreases its crystallinity enabling the access of the enzyme to the hydrolysable chemical bonds. When the alkali pre-treatment is incorporated into the enzymatic process the degradation yields increase more than one order of magnitude reaching values comparable to those obtained during heating/cooling cycles. Our results show energetic advantages over other reported pre-treatments and open new avenues for sustainable PET recycling.

Long Non-Coding RNAs, Extracellular Vesicles and Inflammation in Alzheimer's Disease.

Alzheimer's Disease (AD) has currently no effective treatment; however, preventive measures have the potential to reduce AD risk. Thus, accurate and early prediction of risk is an important strategy to alleviate the AD burden. Neuroinflammation is a major factor prompting the onset of the disease. Inflammation exerts its toxic effect via multiple mechanisms. Amongst others, it is affecting gene expression via modulation of non-coding RNAs (ncRNAs), such as miRNAs. Recent evidence supports that inflammation can also affect long non-coding RNA (lncRNA) expression. While the association between miRNAs and inflammation in AD has been studied, the role of lncRNAs in neurodegenerative diseases has been less explored. In this review, we focus on lncRNAs and inflammation in the context of AD. Furthermore, since plasma-isolated extracellular vesicles (EVs) are increasingly recognized as an effective monitoring strategy for brain pathologies, we have focused on the studies reporting dysregulated lncRNAs in EVs isolated from AD patients and controls. The revised literature shows a positive association between pro-inflammatory lncRNAs and AD. However, the reports evaluating lncRNA alterations in EVs isolated from the plasma of patients and controls, although still limited, confirm the value of specific lncRNAs associated with AD as reliable biomarkers. This is an emerging field that will open new avenues to improve risk prediction and patient stratification, and may lead to the discovery of potential novel therapeutic targets for AD.

Probiotics Treatment Can Improve Cognition in Patients with Mild Cognitive Impairment: A Systematic Review.

BACKGROUND: In recent years, the existence of the gut-brain axis and the impact of intestinal microbiota on brain function has received much attention. Accumulated evidence has prompted the postulation of the infectious hypothesis underlying or facilitating neurodegenerative diseases, such as Alzheimer's disease. Under this hypothesis, intervention with probiotics could be useful at a preventive and therapeutic level. OBJECTIVE: The objective of this systematic review is to reveal a benefit of improved cognitive function following the use of probiotics in individuals with mild cognitive impairment. METHODS: We searched bibliographic databases and analyzed in detail the evidence and methodological quality of five recent randomized, double-blind, placebo-controlled clinical trials using the Cochrane Tool and the SIGN checklist. RESULTS: Overall, and with satisfactory methodological quality, the evaluated studies support the use of probiotics as a weapon to slow the progression of cognitive decline in subjects with mild cognitive impairment. The reviewed literature also indicates that maximum benefit of probiotics is found in subjects with incipient cognitive dysfunction and has no effect in those with advanced disease or absence of disease. CONCLUSION: These results support the intervention with probiotics, especially as a preventive approach. However, caution is required in the interpretation of the results as microbiota has not been evaluated in all studies, and further large-scale research with a prolonged study period is necessary to ensure the translatability of the results into real practice.

Prediction of Alzheimer's Disease by a Novel Image-Based Representation of Gene Expression.

Early intervention can delay the progress of Alzheimer's Disease (AD), but currently, there are no effective prediction tools. The goal of this study is to generate a reliable artificial intelligence (AI) model capable of detecting the high risk of AD, based on gene expression arrays from blood samples. To that end, a novel image-formation method is proposed to transform single-dimension gene expressions into a discriminative 2-dimensional (2D) image to use convolutional neural networks (CNNs) for classification. Three publicly available datasets were pooled, and a total of 11,618 common genes' expression values were obtained. The genes were then categorized for their discriminating power using the Fisher distance (AD vs. control (CTL)) and mapped to a 2D image by linear discriminant analysis (LDA). Then, a six-layer CNN model with 292,493 parameters were used for classification. An accuracy of 0.842 and an area under curve (AUC) of 0.875 were achieved for the AD vs. CTL classification. The proposed method obtained higher accuracy and AUC compared with other reported methods. The conversion to 2D in CNN offers a unique advantage for improving accuracy and can be easily transferred to the clinic to drastically improve AD (or any disease) early detection.

Multispecies fishways in a Mediterranean river: Contributions as migration corridors and compensatory habitat for fish.

River connectivity is essential for the resilience of fish assemblages and populations and is a priority goal to reach good ecological status for river systems. Increasing knowledge on the functionality of restoration tools such as fishways is relevant for future management strategies. The present two-year assessment showed clear ecological contributions of different types of multispecies fishways in the fish assemblage of a strongly modified Mediterranean-type river. Just after their implementation, early and extended use by dominant river-resident fish of both naturelike and technical fishways were observed. All fishways were used in different seasons, especially during the migratory periods by potamodromous cyprinids, suggesting a possible use as migration corridors. Fishways also may provide compensatory habitats for small and juvenile individuals throughout the annual cycles, mostly for rheophilic fish inside nature-like bypasses and for limnophilics inside technical types. Fluvial habitat characteristics and lower flow variability inside the fishways could favour their role as a fish refuge, mainly to juveniles of cyprinids, in heavily regulated rivers where large flow fluctuations occurred. Nature-like fishways could be a better option to function as a compensatory habitat for rheophilic cyprinids in Mediterranean-type Rivers, even more because their use by large nonnative limnophilics seems to be very scarce. However, technical fishways could offer the opportunity to establish control traps of some nonnative fish, which could be of interest to reduce the risk of spreading invasive fish. Therefore, fish ecology and local hydrology should drive the decision between the types to implement. The obtained information on the ecological functionality of multispecies fishways should be considered for applying successful river restorations that are demanded by water and wildlife management schemes (e.g., the European Water Framework Directive).

IRS1 expression in hippocampus is age-dependent and is required for mature spine maintenance and neuritogenesis.

Insulin and insulin-like growth factor type I (IGF-1) play prominent roles in brain activity throughout the lifespan. Insulin/IGF1 signaling starts with the activation of the intracellular insulin receptor substrates (IRS). In this work, we performed a comparative study of IRS1 and IRS2, together with the IGF1 (IGF1R) and insulin (IR) receptor expression in the hippocampus and prefrontal cortex during development. We found that IRS1 and IRS2 expression is prominent during development and declines in the aged hippocampus, contrary to IR, which increases in adulthood and aging. In contrast, IGF1R expression is unaffected by age. Expression patterns are similar in the prefrontal cortex. Neurite development occurs postnatally in the rodent hippocampus and cortex, and it declines in the mature and aged brain and is influenced by trophic factors. In our previous work, we demonstrated that knockdown of IRS1 by shRNA impairs learning and reduces synaptic plasticity in a rat model, as measured by synaptophysin puncta in axons. In this study, we report that shIRS1 alters spine maturation in adult hilar hippocampal neurons. Lastly, to understand the role of IRS1 in neuronal neurite tree, we transfect shIRS1 into primary neuronal cultures and observed that shIRS1 reduced neurite branching and neurite length. Our results demonstrate that IRS1/2 and insulin/IGF1 receptors display different age-dependent expression profiles and that IRS1 is required for spine maturation, demonstrating a novel role for IRS1 in synaptic plasticity.

Neuroinflammation as a possible link between attention-deficit/hyperactivity disorder (ADHD) and pain.

Attention-deficit/hyperactivity disorder (ADHD) and pathological pain are two complex syndromes of multifactorial origin. Despite their prevalence and broad impacts, these conditions are seldom recognized and managed simultaneously. The co-existence of neuropsychiatric conditions (such as ADHD) and altered pain perception and chronic pain has been noted in children, and the comorbidity of ADHD and chronic pain is well documented in adults. Pathophysiological studies have suggested dysfunction of the dopaminergic system as a common neurochemical basis for comorbid ADHD and pain. Considerable evidence supports the role of neuroinflammation in the pathophysiology of both. We suggest that central neuroinflammation underlies altered pain perception and pain sensitization in persons with ADHD. Based on our hypothesis, targeting neuroinflammation may serve as a potential new therapeutic intervention to treat ADHD and comorbid pain in children and adolescents and a preventive strategy for the development of chronic pain in adults with ADHD.

A case of pemphigus herpetiformis with excellent response to mycophenolate mofetil.

Pemphigus herpetiformis (PH) is a rare and unique clinical form of pemphigus foliaceus and pemphigus vulgaris. Patients show autoantibodies against desmoglein 1 and less frequently against desmoglein 3 and desmocollins. We report a 24-year-old woman with a 3-year history of recurrent intensely pruritic erythematous papules and annular plaques localized on the trunk and extremities. In recent months she developed small vesicles around the annular lesions. The histological features showed eosinophilic spongiosis, and direct immunofluorescence demonstrated typical staining of the epidermal intercellular spaces characteristic for pemphigus. There was no mucosal involvement, and hence a diagnosis of PH was established. This patient was unresponsive to dapsone and methotrexate, but she finally experienced remission with prednisone and mycophenolate mofetil.

AAV delivery of shRNA against IRS1 in GABAergic neurons in rat hippocampus impairs spatial memory in females and male rats.

Brain insulin resistance is a major factor leading to impaired cognitive function and it is considered as the onset of Alzheimer´s disease. Insulin resistance is intimately linked to inflammatory conditions, many studies have revealed how pro-inflammatory cytokines lead to insulin resistance, by inhibiting IRS1 function. Thus, the dysfunction of insulin signaling is concomitant with inflammatory biomarkers. However, the specific effect of IRS1 impaired function in otherwise healthy brain has not been dissected out. So, we decided in our study, to study the specific role of IRS1 in the hippocampus, in the absence of comorbidities. To that end, shRNA against rat and human IRS1 was designed and tested in cultured HEK cells to evaluate mRNA levels and specificity. The best candidate sequence was encapsulated in an AAV vector (strain DJ8) under the control of the cytomegalovirus promoter and together with the green fluorescent protein gene as a reporter. AAV-CMV-shIRS1-EGFP and control AAV-CMV-EGFP were inoculated into the dorsal hippocampus of female and male Wistar rats. One month later, animals undertook a battery of behavioral paradigms evaluating spatial and social memory and anxiety. Our results suggest that females displayed increased susceptibility to AAV-shIRS1 in the novel recognition object paradigm; whereas both females and males show impaired performance in the T maze when infected with AAV-shIRS1 compared to control. Anxiety parameters were not affected by AAV-shIRS1 infection. We observed specific fluorescence within the hilum of the dentate gyrus, in immuno-characterized parvalbumin and somatostatin neurons. AAV DJ8 did not enter astrocytes. Intense green fibers were found in the fornix, mammillary bodies, and in the medial septum indicating that hippocampal efferent had been efficiently targeted by the AAV DJ8 infection. We observed that AAV-shIRS1 reduced significantly synaptophysin labeling in hippocampal-septal projections compared to controls. These results support that, small alterations in the insulin/IGF1 pathway in specific hippocampal circuitries can underlie alterations in synaptic plasticity and affect behavior, in the absence of inflammatory conditions.

Adolescent binge-ethanol accelerates cognitive impairment and ß-amyloid production and dysregulates endocannabinoid signaling in the hippocampus of APP/PSE mice.

Previous research in rodents suggests that the long-term neurobehavioral disturbances induced by chronic ethanol (EtOH) exposure could be due to endocannabinoid system (ECS) alterations. Moreover, ECS failure has been proposed to mediate the cognitive impairment and ß-amyloid production in Alzheimer disease (AD). Thus, in the present study, we evaluated the effects of adolescent EtOH binge drinking on the cognitive disturbances, hippocampal ß-amyloid levels, and in the ECS expression on a transgenic mouse model (APP/PSEN, AZ) of AD. We exposed AZ and wild-type mice to a binge-drinking treatment during adolescence. At 6 and 12 months of age, we evaluated hippocampal-dependent learning and memory: ß-amyloid concentrations and RNA and protein levels of cannabinoid type-2 receptors (CB2), diacylglycerol lipase-α (DAGLα), and monoacylglycerol lipase (MAGL) in the hippocampus. The results showed that binge-EtOH treatment worsens cognitive function and increases ß-amyloid levels in AZ. At 6 months, EtOH heightens CB2 (RNA and protein) and DAGLα (RNA) expression in wild type but not in AZ. On the contrary, EtOH enhances MAGL RNA expression only in AZ. At 12 months, AZ displays increased levels of CB2 (RNA and protein) and DAGLα (protein) compared with control. Similar to what happens at 6 months, EtOH induces an increase in CB2 gene expression in wild type but not in AZ; however, it augments CB2 and DAGLα protein levels in both genotypes. Therefore, we propose that adolescent binge drinking accelerates cognitive deficits associated with aging and AD. It also accelerates hippocampal ß-amyloid accumulation in AZ and affects differently the ECS response in wild type and AZ.

Can We Treat Neuroinflammation in Alzheimer's Disease?

Alzheimer's disease (AD), considered the most common type of dementia, is characterized by a progressive loss of memory, visuospatial, language and complex cognitive abilities. In addition, patients often show comorbid depression and aggressiveness. Aging is the major factor contributing to AD; however, the initial cause that triggers the disease is yet unknown. Scientific evidence demonstrates that AD, especially the late onset of AD, is not the result of a single event, but rather it appears because of a combination of risk elements with the lack of protective ones. A major risk factor underlying the disease is neuroinflammation, which can be activated by different situations, including chronic pathogenic infections, prolonged stress and metabolic syndrome. Consequently, many therapeutic strategies against AD have been designed to reduce neuro-inflammation, with very promising results improving cognitive function in preclinical models of the disease. The literature is massive; thus, in this review we will revise the translational evidence of these early strategies focusing in anti-diabetic and anti-inflammatory molecules and discuss their therapeutic application in humans. Furthermore, we review the preclinical and clinical data of nutraceutical application against AD symptoms. Finally, we introduce new players underlying neuroinflammation in AD: the activity of the endocannabinoid system and the intestinal microbiota as neuroprotectors. This review highlights the importance of a broad multimodal approach to treat successfully the neuroinflammation underlying AD.

Functional response of fish assemblage to multiple stressors in a highly regulated Mediterranean river system.

Mediterranean rivers are characterised by strong environmental constrains and species-poor, highly endemic fish fauna. In Europe, these systems are exposed to multiple stressors due to extensive human activities. Studies on the effects of some stressors on riverine fish are available but complex responses of fish assemblages to interplay of flow alteration with physical habitat changes and invasive species have not been evaluated up to date. This study analysed the response of functional diversity of fish assemblages to multiple stressors in the Segura River system in the southern Spain. Fish assemblages were sampled in 16 sites in two consecutive periods (2009-2010 and 2013-2015). Subsequently, we assessed the responses of functional specialisation, originality and entropy (based on nine functional traits and abundances) as well as species richness and abundance to interplay of flow regime alteration and ecological status, fragmentation as well as non-native species abundance across spatial and temporal scales. The governing role of flow regime in structuring fish assemblage was superimposed on physical habitat changes, water quality deterioration and fragmentation as well as the presence of non-native fish species. We found an increase of species richness and abundance but decrease of functional specialisation and originality in river reaches with high level of base flow and more stable hydrological conditions. Opposite pattern was observed in reaches with severe reduction of base flow and marked inversion in the seasonal pattern of high and low flows. We postulate that the use of tools that consider the functional identity of the species as method to assess the effects of environmental alterations on fish biodiversity could improve conservation measures for Mediterranean fish fauna. Furthermore, design flows that mimic natural flow regime patterns characteristic for Mediterranean rivers are a promising tool to provide environmental conditions that would favour native fish within the assemblage and benefit their conservation.

Early intervention with ABA prevents neuroinflammation and memory impairment in a triple transgenic mice model of Alzheimer´s disease.

Neuroinflammation and insulin resistance in the brain are intimately linked to neurodegenerative disorders, including Alzheimer's disease. Even though traditionally Alzheimer´s disease has been associated to Aß deposits and hyperphosphorylated Tau intracellular tangles, several studies show that neuroinflammation may be the initial cause that triggers degeneration. Accordingly, a number of natural supplements that improves brain insulin sensitivity and reduce neuroinflammation have been proposed as good choices in the therapeutic prevention of cognitive decline. Further supporting this evidence, we show that phytohormone Abscisic Acid, can prevent memory impairment and neuroinflammation markers in a triple transgenic mouse model, where no peripheral inflammatory changes have occurred. Moreover, our data strongly suggests that early intervention is critical for good prognosis, and that cognitive improvement requires longer treatment than recovering neuroinflammation markers.

Correction to: Abscisic Acid Supplementation Rescues High Fat Diet-Induced Alterations in Hippocampal Inflammation and IRSs Expression.

The author missed to include the second affiliation of Mariam Atef to the original paper published. With this, the authors published this correction.

Abscisic Acid Supplementation Rescues High Fat Diet-Induced Alterations in Hippocampal Inflammation and IRSs Expression.

Accumulated evidence indicates that neuroinflammation induces insulin resistance in the brain. Moreover, both processes are intimately linked to neurodegenerative disorders, including Alzheimer's disease. Potential mechanisms underlying insulin resistance include serine phosphorylation of the insulin receptor substrate (IRS) or insulin receptor (IR) misallocation. However, only a few studies have focused on IRS expression in the brain and its modulation in neuroinflammatory processes. This study used the high-fat diet (HFD) model of neuroinflammation to study the alterations of IR, an insulin-like growth factor receptor (IGF1R) and IRS expressions in the hippocampus. We observed that HFD effectively reduced mRNA and protein IRS2 expression. In contrast, a HFD induced the upregulation of the IRS1 mRNA levels, but did not alter an IR and IGF1R expression. As expected, we observed that a HFD increased hippocampal tumor necrosis factor alpha (TNFα) and amyloid precursor protein (APP) levels while reducing brain-derived neurotrophic factor (BDNF) expression and neurogenesis. Interestingly, we found that TNFα correlated positively with IRS1 and negatively with IRS2, whereas APP levels correlated positively only with IRS1 but not IRS2. These results indicate that IRS1 and IRS2 hippocampal expression can be affected differently by HFD-induced neuroinflammation. In addition, we aimed to establish whether abscisic acid (ABA) can rescue hippocampal IRS1 and IRS2 expression, as we had previously shown that ABA supplementation prevents memory impairments and improves neuroinflammation induced by a HFD. In this study, ABA restored HFD-induced hippocampal alterations, including IRS1 and IRS2 expression, TNFα, APP, and BDNF levels and neurogenesis. In conclusion, this study highlights different regulations of hippocampal IRS1 and IRS2 expression using a HFD, indicating the important differences of these scaffolding proteins, and strongly supports ABA therapeutic effects.

Central relaxin-3 receptor (RXFP3) activation impairs social recognition and modulates ERK-phosphorylation in specific GABAergic amygdala neurons.

In mammals, the extended amygdala is a neural hub for social and emotional information processing. In the rat, the extended amygdala receives inhibitory GABAergic projections from the nucleus incertus (NI) in the pontine tegmentum. NI neurons produce the neuropeptide relaxin-3, which acts via the Gi/o-protein-coupled receptor, RXFP3. A putative role for RXFP3 signalling in regulating social interaction was investigated by assessing the effect of intracerebroventricular infusion of the RXFP3 agonist, RXFP3-A2, on performance in the 3-chamber social interaction paradigm. Central RXFP3-A2, but not vehicle, infusion, disrupted the capacity to discriminate between a familiar and novel conspecific subject, but did not alter differentiation between a conspecific and an inanimate object. Subsequent studies revealed that agonist-infused rats displayed increased phosphoERK(pERK)-immunoreactivity in specific amygdaloid nuclei at 20 min post-infusion, with levels similar to control again after 90 min. In parallel, we used immunoblotting to profile ERK phosphorylation dynamics in whole amygdala after RXFP3-A2 treatment; and multiplex histochemical labelling techniques to reveal that after RXFP3-A2 infusion and social interaction, pERK-immunopositive neurons in amygdala expressed vesicular GABA-transporter mRNA and displayed differential profiles of RXFP3 and oxytocin receptor mRNA. Overall, these findings demonstrate that central relaxin-3/RXFP3 signalling can modulate social recognition in rats via effects within the amygdala and likely interactions with GABA and oxytocin signalling.