CREB regulates the expression of neuronal glucose transporter 3: a possible mechanism related to impaired brain glucose uptake in Alzheimer’s disease

Impaired brain glucose uptake and metabolism precede the appearance of clinical symptoms in Alzheimer disease (AD). Neuronal glucose transporter 3 (GLUT3) is decreased in AD brain and correlates with tau pathology. However, what leads to the decreased GLUT3 is yet unknown. In this study, we found that the promoter of human GLUT3 contains three potential cAMP response element (CRE)-like elements, CRE1, CRE2 and CRE3. Overexpression of CRE-binding protein (CREB) or activation of cAMP-dependent protein kinase significantly increased GLUT3 expression. CREB bound to the CREs and promoted luciferase expression driven by human GLUT3-promoter. Among the CREs, CRE2 and CRE3 were required for the promotion of GLUT3 expression. Full-length CREB was decreased and truncation of CREB was increased in AD brain. This truncation was correlated with calpain I activation in human brain. Further study demonstrated that calpain I proteolysed CREB at Gln₂₈–Ala₂₉ and generated a 41-kDa truncated CREB, which had less activity to promote GLUT3 expression. Importantly, human brain GLUT3 was correlated with full-length CREB positively and with activation of calpain I negatively. These findings suggest that overactivation of calpain I caused by calcium overload proteolyses CREB, resulting in a reduction of GLUT3 expression and consequently impairing glucose uptake and metabolism in AD brain.     

A review of major Crohn’s disease susceptibility genes and their role in disease pathogenesis

Crohn’s disease (CD) is a chronic inflammatory bowel disease whose relevance is increasing in industrialized society. Recent genome wide association studies revealed over seventy one loci associated with disease penetrance. Several variants that increase disease risk encode for altered proteins that diminish bacterial host defense. NOD2 alters intracellular bacterial sensing while ATG16L1 is thought to diminish bacterial clearance by impairing autophagy. Additionally, changes in the IBD5 locus are thought to diminish barrier function. Alternatively, recent data indicate a gain of function genetic variant of IL23R is protective amongst European CD patients. These recent genetic discoveries contradict historical theories that Crohn’s disease results from overactive auto-aggressive responses. Rather, new genetic data suggest disease-associated variants encode for dysfunctional proteins that diminish essential innate immune responses against commensal organisms. This review provides an overview of these critical discoveries and places them in their biological context.     

Chasing genes in Alzheimer’s and Parkinson’s disease

Alzheimers disease (AD), the most common type of dementia, and Parkinsons disease (PD), the most common movement disorder, are both neurodegenerative adult-onset diseases characterized by the progressive loss of specific neuronal populations and the accumulation of intraneuronal inclusions. The search for genetic and environmental factors that determine the fate of neurons during the ageing process has been a widespread approach in the battle against neurodegenerative disorders. Genetic studies of AD and PD initially focused on the search for genes involved in the aetiological mechanisms of monogenic forms of these diseases. They later expanded to study hundreds of patients, affected relative-pairs and population-based studies, sometimes performed on special isolated populations. A growing number of genes (and pathogenic mutations) is being identified that cause or increase susceptibility to AD and PD. This review discusses the way in which strategies of gene hunting have evolved during the last few years and the significance of finding genes such as the presenilins, -synuclein, parkin and DJ-1. In addition, we discuss possible links between these two neurodegenerative disorders. The clinical, pathological and genetic presentation of AD and PD suggests the involvement of a few overlapping interrelated pathways. Their imbricate features point to a spectrum of neurodegeneration (tauopathies, synucleinopathies, amyloidopathies) that need further intense investigation to find the missing links.     

Intestinal expression of metal transporters in Wilson’s disease

In Wilson’s disease (WND), biallelic ATP7B gene mutation is responsible for pathological copper accumulation in the liver, brain and other organs. It has been proposed that copper transporter 1 (CTR1) and the divalent metal transporter 1 (DMT1) translocate copper across the human intestinal epithelium, while Cu-ATPases: ATP7A and ATP7B serve as copper efflux pumps. In this study, we investigated the expression of CTR1, DMT1 and ATP7A in the intestines of both WND patients and healthy controls to examine whether any adaptive mechanisms to systemic copper overload function in the enterocytes. Duodenal biopsy samples were taken from 108 patients with Wilson’s disease and from 90 controls. CTR1, DMT1, ATP7A and ATP7B expression was assessed by polymerase chain reaction and Western blot. Duodenal CTR1 mRNA and protein expression was decreased in WND patients in comparison to control subjects, while ATP7A mRNA and protein production was increased. The variable expression of copper transporters may serve as a defense mechanism against systemic copper overload resulting from functional impairment of ATP7B.     

Hsp60 and Hsp10 increase in colon mucosa of Crohn’s disease and ulcerative colitis

The purpose of this work was to determine in colon mucosa of Crohn’s disease (CD) and ulcerative colitis (UC) in relapse: a) the levels of the chaperonins Hsp60 and Hsp10; b) the quantity of inflammatory cells; and c) if the levels of chaperonins parallel those of inflammation cells. Twenty cases of CD and UC and twenty normal controls (NC) were studied using immunohistochemistry, Western blotting and immunofluorescence. Immunohistochemically, Hsp60 and Hsp10 were increased in both inflammatory bowel diseases (IBD) compared to NC. These results were confirmed by Western blotting. Hsp60 and Hsp10 occurred in the cytoplasm of epithelial cells in CD and UC but not in NC. Hsp60 and Hsp10 co-localised to epithelial cells of mucosal glands but not always in connective tissue cells of lamina propria, where only Hsp60 or, less often, Hsp10 was found. Cells typical of inflammation were significantly more abundant in CD and UC than in NC. Since chaperonins are key factors in the activation of the immune system leading to inflammation, we propose that they play a central role in the pathogenesis of the two diseases, which, consequently, ought to be studied as chaperonopathies.     

Sensory evoked and event related oscillations in Alzheimer’s disease: a short review

Diagnosis and treatment of Alzheimer’s disease (AD) depend on clinical evaluation and there is a strong need for an objective tool as a biomarker. Our group has investigated brain oscillatory responses in a small group of AD subjects. We found that the de novo (untreated) AD group differs from both the cholinergically-treated AD group and aged-matched healthy controls in theta and delta responses over left frontal-central areas after cognitive stimulation. On the contrary, the difference observed in AD groups upon a sensory visual stimulation includes response increase over primary or secondary visual sensorial areas compared to controls. These findings imply at least two different neural networks, depending on type of stimulation (i.e. cognitive or sensory). The default mode defined as activity in resting state in AD seems to be affected electrophysiologically. Coherences are also very valuable in observing the group differences, especially when a cognitive stimulus is applied. In healthy controls, higher coherence values are elicited after a cognitive stimulus than after a sensory task. Our findings support the notion of disconnectivity of cortico-cortical connections in AD. The differences in comparison of oscillatory responses upon sensory and cognitive stimulations and their role as a biomarker in AD await further investigation in series with a greater number of subjects.     

Association between genome-wide association studies reported SNPs and pediatric-onset Crohn’s disease in Canadian children

A recent pediatric-focused genome-wide association study has implicated three novel susceptibility loci for Crohn’ disease (CD).We aimed to investigate whether the three recently reported and other previously reported genes/loci were also associated with CD in Canadian children. A case–control design was implemented at three pediatric gastroenterology clinics in Canada. Children <19 years of age with a confirmed diagnosis of CD were recruited along with controls. Single nucleotide polymorphisms (SNPs) in 19 reported genes/loci were genotyped. Associations between individual SNPs and CD were examined. A total of 563 cases and 553 controls were studied. The mean (±SD) age of the cases was 12.3 (±3.2) years. Most cases were male (56.0%), had ileo-colonic disease (L3 ± L4, 48.8%) and inflammatory behavior (B1 ± p, 87.9%) at diagnosis. Allelic association analysis (two-tailed) showed that 8 of the 19 targeted SNPs were significantly associated with overall susceptibility for CD. Associations with one additional SNP was borderline non-significant. Significantly associated SNPs included SNPs rs1250550 (p = 0.026) and rs8049439 (p = 0.04), recently reported to be specifically associated with pediatric-onset CD.Based on the results, we confirmed associations between two of the three novel pediatric-CD loci and other regions reported for associations with either pediatric and/or adult-onset CD.     

Identifying candidate genes for discrimination of ulcerative colitis and Crohn’s disease

In this study we aimed to screen effective biomarkers for differential diagnosis of ulcerative colitis (UC) and Crohn’s disease (CD). By using the gene expression profile dataset GSE24287 including 47 ileal CD, 27 UC and 25 non-inflammatory bowel diseases control downloaded from Gene Expression Omnibus database, we identified the differentially expressed genes (DEGs) between UC patients and controls as well as between CD patients and controls (|log₂FC(fold change)| > 1 and p < 0.05). Then Gene Ontology (GO) functional enrichment analyses were performed for these DEGs in two groups, followed by the construction of weight PPI (protein–protein interaction) networks. Subnets enriched for the PPIs and differentially expressed genes were constructed based on the weight PPI networks. The overlapping genes between the genes in the top 10 subnets with smallest p value and the DEGs were selected as the candidate genes of disease. A total of 75 DEGs were identified in UC group and 87 ones in CD group. There were 69 and 57 specific DEGs in CD group and UC group, respectively. The DEGs in CD group were mainly enriched in “inflammatory response” and “defense response”, while the most significantly enriched GO terms in UC group were “anion transport” and “chemotaxis”. FOS and SOCS3 were identified as candidate genes for CD and other three genes HELB, ZBTB16 and FAM107A were candidate genes for UC. In conclusion, there were distinct genetic alterations between UC and CD. The candidate genes identified in current study may be used as biomarkers for differential diagnosis of CD and UC.     

Alzheimer’s disease related genes during primate evolution

During primate evolution, the neuronal and cognition-related genes have evolved rapidly. These genes seem to induce neurological illnesses such as Alzheimer’s disease (AD). In this study, we analyzed genes APOE, TOMM40, and PICALM known as the risk factors of AD. We performed bioinformatics analyses in relation to evolution, phylogeny, and protein structure for those genes in humans, Neanderthals, chimpanzees, bonobos, gorillas, orangutans, crab-eating monkeys, and rhesus monkeys. Cholesterol-related genes showed relatively rapid evolution toward a lower risk of AD. Neanderthals showed relatively higher polymorphism in genes APOE, TOMM40, and PICALM than humans did. Phylogeny indicated different topologies in the trichotomy of humans, chimpanzees, and gorillas in terms of genes APOE, TOMM40, and PICALM. These results provide to hominin-specific patterns in three genes, and give clues to the modern human-specific traits of AD and shed light on further functional research helping to understand AD.     

α-Synuclein expression selectively affects tumorigenesis in mice modeling Parkinson's disease

Alpha Synuclein (α-Syn) is a protein implicated in mechanisms of neuronal degeneration in Parkinson's disease (PD). α-Syn is primarily a neuronal protein, however, its expression is found in various tumors including ovarian, colorectal and melanoma tumors. It has been hypothesized that neurodegeneration may share common mechanisms with oncogenesis. We tested whether α-Syn expression affects tumorigenesis of three types of tumors. Specifically, B16 melanoma, E0771 mammary gland adenocarcinoma and D122 Lewis lung carcinoma. For this aim, we utilized transgenic mice expression the human A53T α-Syn form. We found that the in vivo growth of B16 and E0771 but not D122 was enhanced in the A53T α-Syn mice. The effect on tumorigenesis was not detected in age-matched APP/PS1 mice, modeling Alzheimer's disease (AD), suggesting a specific effect for α-Syn-dependent neurodegeneration. Importantly, transgenic α-Syn expression was detected within the three tumor types. We further show uptake of exogenously added, purified α-Syn, by the cultured tumor cells. In accord, with the affected tumorigenesis in the young A53T α-Syn mice, over-expression of α-Syn in cultured B16 and E0771 cells enhanced proliferation, however, had no effect on the proliferation of D122 cells. Based on these results, we suggest that certain forms of α-Syn may selectively accelerate cellular mechanisms leading to cancer.     

Blood–brain-barriers in aging and in Alzheimer’s disease

The aging process correlates with a progressive failure in the normal cellular and organ functioning; these alterations are aggravated in Alzheimer’s disease (AD). In both aging and AD there is a general decrease in the capacity of the body to eliminate toxic compounds and, simultaneously, to supply the brain with relevant growth and nutritional factors. The barriers of the brain are targets of this age related dysfunction; both the endothelial cells of the blood–brain barrier and the choroid plexus epithelial cells of the blood-cerebrospinal fluid barrier decrease their secretory capacity towards the brain and their ability to remove toxic compounds from the brain. Additionally, during normal aging and in AD, the permeability of the brain barriers increase. As such, a greater contact of the brain parenchyma with the blood content alters the highly controlled neural environment, which impacts on neural function. Of interest, the brain barriers are more than mere obstacles to the passage of molecules and cells, and therefore active players in brain homeostasis, which is still to be further recognized and investigated in the context of health and disease. Herein, we provide a review on how the brain barriers change during aging and in AD and how these processes impact on brain function.     

Glutamate and Parkinson’s disease

Altered glutamatergic neurotransmission and neuronal metabolic dysfunction appear to be central to the pathophysiology of Parkinson’s disease (PD). The substantia nigra pars compacta—the area where the primary pathological lesion is located—is particularly exposed to oxidative stress and toxic and metabolic insults. A reduced capacity to cope with metabolic demands, possibly related to impaired mitochondrial function, may render nigral neurons highly vulnerable to the effects of glutamate, which acts as a neurotoxin in the presence of impaired cellular energy metabolism. In this way, glutamate may participate in the pathogenesis of PD. Degeneration of dopamine nigral neurons is followed by striatal dopaminergic denervation, which causes a cascade of functional modifications in the activity of basal ganglia nuclei. As an excitatory neurotransmitter, glutamate plays a pivotal role in normal basal ganglia circuitry. With nigrostriatal dopaminergic depletion, the glutamatergic projections from subthalamic nucleus to the basal ganglia output nuclei become overactive and there are regulatory changes in glutamate receptors in these regions. There is also evidence of increased glutamatergic activity in the striatum. In animal models, blockade of glutamate receptors ameliorates the motor manifestations of PD. Therefore, it appears that abnormal patterns of glutamatergic neurotransmission are important in the symptoms of PD. The involvement of the glutamatergic system in the pathogenesis and symptomatology of PD provides potential new targets for therapeutic intervention in this neuro-degenerative disorder.     

Perianal Crohn’s disease and hidradenitis suppurativa: a possible common immunological scenario

Background

Crohn’s disease (CD) and Hidradenitis suppurativa (HS) are both chronic inflammatory diseases. The pathogenesis of these diseases is multifactorial, due to the interaction of genetic and environmental factors leading to a deregulated local immune response where T lymphocytes play a major role. To the best of our knowledge, no previous study has clarified whether the pathogenetic mechanism of perianal CD and HS is the same. We therefore analyzed the cellular expression pattern and the cytokine repertoire in three patients suffering from both perianal CD and HS.

Methods

We evaluated three patients affected by concurrent HS and CD with fistulizing perianal disease. Surgical specimens have been fixed and embedded in paraffin prior to sectioning for histological examination. Inflammatory tissue curettages have been recovered during intervention from perianal fistulas and HS lesions in order to analyze the phenotypic and functional characteristics of infiltrating T cells. In particular we evaluated T cells, by flow cytometry, for cytokine production profile and expression of surface markers. Moreover, analysis of the T cell repertoire was performed by means of spectratyping, in only one patient.

Results

A higher frequency of CD4+ CD161+ T lymphocytes has been detected in CD fistulas and in HS lesions than in peripheral blood (PB) samples. In the patient in whom we derived enough cells from the three sources, we found higher frequency of CD4+ IL-17- producing cells in HS lesion and fistula lesion compared to PB. It is noteworthy that the same clonotypes were expanded in this patient in T cells derived from both HS lesion and fistula lesion.

Conclusion

The presence of numerous CD4+ CD161+ lymphocytes in fistula and HS lesion curettages suggests that these cells may play a pathogenic role, and candidates CD161 as a possible biological target for medical treatment.