Erika Gyengesi

Peroxisome proliferation-associated control of reactive oxygen species sets melanocortin tone and feeding in diet-induced obesity

Previous studies have proposed roles for hypothalamic reactive oxygen species (ROS) in the modulation of circuit activity of the melanocortin system. Here we show that suppression of ROS diminishes pro-opiomelanocortin (POMC) cell activation and promotes the activity of neuropeptide Y (NPY)- and agouti-related peptide (AgRP)-co-producing (NPY/AgRP) neurons and feeding, whereas ROS-activates POMC neurons and reduces feeding. The levels of ROS in POMC neurons were positively correlated with those of leptin in lean and ob/ob mice, a relationship that was diminished in diet-induced obese (DIO) mice. High-fat feeding resulted in proliferation of peroxisomes and elevated peroxisome proliferator–activated receptor γ (PPAR-γ) mRNA levels within the hypothalamus. The proliferation of peroxisomes in POMC neurons induced by the PPAR-γ agonist rosiglitazone decreased ROS levels and increased food intake in lean mice on high-fat diet. Conversely, the suppression of peroxisome proliferation by the PPAR antagonist GW9662 increased ROS concentrations and c-fos expression in POMC neurons. Also, it reversed high-fat feeding–triggered elevated NPY/AgRP and low POMC neuronal firing, and resulted in decreased feeding of DIO mice. Finally, central administration of ROS alone increased c-fos and phosphorylated signal transducer and activator of transcription 3 (pStat3) expression in POMC neurons and reduced feeding of DIO mice. These observations unmask a previously unknown hypothalamic cellular process associated with peroxisomes and ROS in the central regulation of energy metabolism in states of leptin resistance.

Prolylcarboxypeptidase regulates food intake by inactivating α-MSH in rodents

The anorexigenic neuromodulator alpha-melanocyte-stimulating hormone (alpha-MSH; referred to here as alpha-MSH1-13) undergoes extensive posttranslational processing, and its in vivo activity is short lived due to rapid inactivation. The enzymatic control of alpha-MSH1-13 maturation and inactivation is incompletely understood. Here we have provided insight into alpha-MSH1-13 inactivation through the generation and analysis of a subcongenic mouse strain with reduced body fat compared with controls. Using positional cloning, we identified a maximum of 6 coding genes, including that encoding prolylcarboxypeptidase (PRCP), in the donor region. Real-time PCR revealed a marked genotype effect on Prcp mRNA expression in brain tissue. Biochemical studies using recombinant PRCP demonstrated that PRCP removes the C-terminal amino acid of alpha-MSH1-13, producing alpha-MSH1-12, which is not neuroactive. We found that Prcp was expressed in the hypothalamus in neuronal populations that send efferents to areas where alpha-MSH1-13 is released from axon terminals. The inhibition of PRCP activity by small molecule protease inhibitors administered peripherally or centrally decreased food intake in both wild-type and obese mice. Furthermore, Prcp-null mice had elevated levels of alpha-MSH1-13 in the hypothalamus and were leaner and shorter than the wild-type controls on a regular chow diet; they were also resistant to high-fat diet-induced obesity. Our results suggest that PRCP is an important component of melanocortin signaling and weight maintenance via control of active alpha-MSH1-13 levels.

Super-resolution track-density imaging studies of mouse brain: Comparison to histology

The recently proposed track-density imaging (TDI) technique was introduced as a means to achieve super-resolution using diffusion MRI. This technique is able to increase the spatial resolution of the reconstructed images beyond the acquired MRI resolution by incorporating information from whole-brain fibre-tracking results. It not only achieves super-resolution, but also provides very high anatomical contrast with a new MRI contrast mechanism. However, the anatomical information-content of this novel contrast mechanism has not yet been assessed. In this work, we perform such a study using diffusion MRI of ex vivo mouse brains acquired at 16.4 T, to compare the results of the super-resolution TDI technique with histological staining (myelin and Nissl stains) in the same brains. Furthermore, a modified version of the directionally-encoded colour TDI map using short-tracks is introduced, which reduces the TDI intensity dynamic range, and therefore enhances the directionality colour-contrast. Good agreement was observed between structures visualised in the super-resolution TDI maps and in the histological sections, supporting the anatomical information-content of the images generated using the TDI technique. The results therefore show that the TDI methodology does provide meaningful and rich anatomical contrast, in addition to achieving super-resolution. Furthermore, this study is the first to show the application of TDI to mouse brain imaging: the high-resolution, high-quality images demonstrate the useful complementary information that can be achieved using super-resolution TDI.

Novel promising therapeutics against chronic neuroinflammation and neurodegeneration in Alzheimer's disease.

Alzheimers disease (AD) is a progressive neurodegenerative disorder, characterized by deposition of amyloid plaques and neurofibrillary tangles, as well as microglial and astroglial activation, and, finally, leading to neuronal dysfunction and death. Current treatments for AD primarily focus on enhancement of cholinergic transmission. However, these treatments are only symptomatic, and no disease-modifying drug is available for the treatment of AD patients. This review will provide an overview of the antioxidant, anti-inflammatory, anti-amyloidogenic, neuroprotective, and cognition-enhancing effects of a variety of nutraceuticals including curcumin, apigenin, docosahexaenoic acid, epigallocatechin gallate, α-lipoic acid and resveratrol and their potential for AD prevention and treatment. We suggest that therapeutic use of these compounds might lead to a safe strategy to delay the onset of AD or slow down its progression. The continuing investigation of the potential of these substances is necessary as they are promising compounds to yield a possible remedy for this pervasive disease.

Corticosterone regulates synaptic input organization of POMC and NPY/AgRP neurons in adult mice.

Changes in circulating hormones, such as leptin and ghrelin, induce alterations in synaptic input organization and electrophysiological properties of neurons of the arcuate nucleus of the hypothalamus. To assess whether changes in circulating glucocorticoids also alter synaptic arrangement and membrane potential properties, we studied the effect of adrenalectomy (ADX) and corticosterone replacement in mice on the proopiomelanocortin (POMC) and neuropeptide Y (NPY)/agouti-related protein (AgRP) neurons of the hypothalamic arcuate nucleus. ADX reduced the number of symmetric, putative inhibitory synapses onto POMC neurons and the number of asymmetric, putative excitatory synapses onto NPY/AgRP neurons. Corticosterone replacement in ADX mice to levels similar to sham-operated animals restored the number of synapses onto POMC and NPY/AgRP neurons to that seen in sham-operated controls. The alterations in the synaptic arrangement in ADX mice were not due to their decrease in food intake as evidenced by the synaptic analysis of the pair-fed control animals. In line with the altered synaptic input organization, a depolarization of POMC membrane potential and a hyperpolarization of NPY/AgRP membrane potential were observed in ADX mice compared with their sham-operated controls. All of these changes reverted upon corticosterone replacement. These results reveal that the known orexigenic action of corticosteroids is mediated, at least in part, by synaptic changes and altered excitability of the melanocortin system.

The basal forebrain cholinergic projection system in mice

Publisher Summary The basal forebrain is composed of an affiliation of heterogeneous structures and includes the medial septum, ventral pallidum (VP), diagonal band nuclei, substantia innominata/extended amygdala, and peripallidal regions. The basal forebrain is located close to the medial and ventral surfaces of the cerebral hemispheres that develop from the subpallium. This highly complex brain region has been implicated in cortical activation, attention, motivation, memory, and neuropsychiatric disorders such as Alzheimers disease Parkinsons disease, schizophrenia, and drug abuse. The basal forebrain contains a heterogeneous mixture of cell types that differ in transmitter content, morphology, and projection pattern. One of the most prominent features of the mammalian basal forebrain is the presence of a collection of aggregated and non-aggregated, large, hyperchromic neurons, many of them containing choline acetyl transferase (ChAT), the critical enzyme in the synthesis of acetylcholine (ACh); these neurons project to the cerebral cortex. Single unit studies in anesthetized and behaving rats showed that identified cholinergic neurons increase their firing during cortical EEG activation. Activity of basal forebrain cholinergic neurons is associated with an increase in cortical release of ACh. Cortical ACh release is high during wakefulness and rapid eye movement (REM) sleep and is low during non-REM sleep that is characterized by EEG delta power with periodic oscillations of medium-frequency high amplitude spindles. Against the relatively “diffuse” termination of the ascending brainstem and hypothalamic axons in the basal forebrain, the restricted input from the prefrontal cortex to basal forebrain neurons, including specific clusters, might be instrumental in communicating state-related changes from basal forebrain neurons to specific posterior sensory areas to modulate selective cognitive processes.Publisher Summary The basal forebrain is composed of an affiliation of heterogeneous structures and includes the medial septum, ventral pallidum (VP), diagonal band nuclei, substantia innominata/extended amygdala, and peripallidal regions. The basal forebrain is located close to the medial and ventral surfaces of the cerebral hemispheres that develop from the subpallium. This highly complex brain region has been implicated in cortical activation, attention, motivation, memory, and neuropsychiatric disorders such as Alzheimers disease Parkinsons disease, schizophrenia, and drug abuse. The basal forebrain contains a heterogeneous mixture of cell types that differ in transmitter content, morphology, and projection pattern. One of the most prominent features of the mammalian basal forebrain is the presence of a collection of aggregated and non-aggregated, large, hyperchromic neurons, many of them containing choline acetyl transferase (ChAT), the critical enzyme in the synthesis of acetylcholine (ACh); these neurons project to the cerebral cortex. Single unit studies in anesthetized and behaving rats showed that identified cholinergic neurons increase their firing during cortical EEG activation. Activity of basal forebrain cholinergic neurons is associated with an increase in cortical release of ACh. Cortical ACh release is high during wakefulness and rapid eye movement (REM) sleep and is low during non-REM sleep that is characterized by EEG delta power with periodic oscillations of medium-frequency high amplitude spindles. Against the relatively “diffuse” termination of the ascending brainstem and hypothalamic axons in the basal forebrain, the restricted input from the prefrontal cortex to basal forebrain neurons, including specific clusters, might be instrumental in communicating state-related changes from basal forebrain neurons to specific posterior sensory areas to modulate selective cognitive processes.

Curcumin and apigenin : novel and promising therapeutics against chronic neuroinflammation in Alzheimer’s disease

Alzheimer′s disease is a progressive neurodegenerative disorder, characterized by deposition of amyloid beta, neurofibrillary tangles, astrogliosis and microgliosis, leading to neuronal dysfunction and loss in the brain. Current treatments for Alzheimer′s disease primarily focus on enhancement of cholinergic transmission. However, these treatments are only symptomatic, and no disease-modifying drug is available for Alzheimer′s disease patients. This review will provide an overview of the proven antioxidant, anti-inflammatory, anti-amyloidogenic, neuroprotective, and cognition-enhancing effects of curcumin and apigenin and discuss the potential of these compounds for Alzheimer′s disease prevention and treatment. We suggest that these compounds might delay the onset of Alzheimer′s disease or slow down its progression, and they should enter clinical trials as soon as possible.

Chronic Neuroinflammation in Alzheimer’s Disease: New Perspectives on Animal Models and Promising Candidate Drugs

Chronic neuroinflammation is now considered one of the major factors in the pathogenesis of Alzheimers disease (AD). However, the most widely used transgenic AD models (overexpressing mutated forms of amyloid precursor protein, presenilin, and/or tau) do not demonstrate the degree of inflammation, neurodegeneration (particularly of the cholinergic system), and cognitive decline that is comparable with the human disease. Hence a more suitable animal model is needed to more closely mimic the resulting cognitive decline and memory loss in humans in order to investigate the effects of neuroinflammation on neurodegeneration. One of these models is the glial fibrillary acidic protein-interleukin 6 (GFAP-IL6) mouse, in which chronic neuroinflammation triggered constitutive expression of the cytokine interleukin-6 (IL-6) in astrocytes. These transgenic mice show substantial and progressive neurodegeneration as well as a decline in motor skills and cognitive function, starting from 6 months of age. This animal model could serve as an excellent tool for drug discovery and validation in vivo. In this review, we have also selected three potential anti-inflammatory drugs, curcumin, apigenin, and tenilsetam, as candidate drugs, which could be tested in this model.

Natural Compounds and Plant Extracts as Therapeutics Against Chronic Inflammation in Alzheimer's Disease - A Translational Perspective

Alzheimers disease (AD) is a progressive neurodegenerative disorder, characterized by deposition of amyloid beta, neurofibrillary tangles, astrogliosis and microgliosis, leading to neuronal dysfunction and loss in the brain. Bio- and histochemical evidence suggests a pivotal role of central and peripheral inflammation in its aetiopathology, linked to the production of free radicals. Numerous epidemiological studies support that the long-term use of non-steroidal antiinflammatory drugs is preventive against AD, but these medications do not slow down the progression of the disease in already diagnosed patients. There are a number of studies focusing on traditional herbal medicines and small molecules (usually plant secondary metabolites) as potential anti-inflammatory drugs, particulary in respect to cytokine suppression. For instance, ω-3 polyunsaturated fatty acids and a number of polyphenolic phytochemicals have been shown to be effective against inflammation in animal and cell models. Some of these plant secondary metabolites have also been shown to possess antioxidant, anti-inflammatory, anti-amyloidogenic, neuroprotective, and cognition-enhancing effects. This review will provide an overview the effects of catechins/proanthocyanidins from green tea, curcumin from turmeric, extracts enriched in bacosides from Brahmi (Bacopa monnieri), flavone glycosides from Ginkgo biloba, and ω-3 polyunsaturated fatty acids. They do not only counteract one pathophysiological aspect of AD in numerous in vitro and in vivo studies of models of AD, but also ameliorate several of the above mentioned pathologies. The evidence suggests that increased consumption of these compounds might lead to a safe strategy to delay the onset of AD. The continuing investigation of the potential of these substances is necessary as they are promising to yield a possible remedy for this pervasive disease.

Plant polyphenols as inhibitors of NF-κB induced cytokine production—a potential anti-inflammatory treatment for Alzheimer's disease?

Alzheimer’s disease (AD) is a neurodegenerative disorder that impacts the daily lives of many sufferers throughmemory loss as well as behavioral and cognitive changes. AD is themost common form of dementia. One in ten people over the age of 65, and around half of those over 85 have AD. AD can be divided into familial (early-onset) and sporadic (late-onset) cases, with the familial form ( 99% of cases) caused by a variety of genetic (e.g., apolipoprotein E), metabolic and environmental factors. The AD brain is characterized macroscopically by cortical atrophy, caused by degeneration of the cholinergic axonal arborisation and shrinkage of the dendritic tree. Microscopically, amyloid beta peptide deposits (senile plaques) and neurofibrillary tangles are present in affected areas (GilBea et al., 2012). AD is also characterized by chronic neuroinflammation, driven by activation of astroglia and microglia (Rosenblum, 2014). In addition, levels of pro-inflammatory mediators or cytokines which include chemokines, interferons, interleukins, lymphokines, and tumor necrosis factors are elevated in the brains of patients with AD (Latta et al., 2014). Furthermore, nuclear translocation of NF-κB and STAT-1α, transcription factors involved in pro-inflammatory gene expression, indicates the presence of a sustained pro-inflammatory process (Lawrence, 2009).