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Up-regulation of adenosine receptors in the frontal cortex in Alzheimer's disease.

ABSTRACT: Adenosine receptors are G-protein coupled receptors which modulate neurotransmitter release, mainly glutamate. Adenosine A(1) and A(2A) receptors were studied in post-mortem human cortex in Alzheimer's disease (AD) and age-matched controls. Total adenosine A(1) receptor number, determined by radioligand binding assay, using [(3)H]DPCPX, was significantly increased in AD cases in early and advanced stages without differences with the progression of the disease. A significant increase of A(1)R (37 kDa) levels was also observed by Western blot in early and advanced stages of AD. In addition, increased numbers of adenosine A(2A) receptors were observed in AD samples as determined by a binding assay using [(3)H]ZM 241385 as a radioligand and by Western blot. Increased binding and protein expression levels of adenosine receptors were not associated with increased mRNA levels coding A(1) and A(2A) receptors. Finally, increased A(1) and A(2A) receptor-mediated response was observed. These results show up-regulation of adenosine A(1) and A(2A) receptors in frontal cortex in AD, associated with sensitization of the corresponding transduction pathways.

SUBMITTER: Albasanz JL

PROVIDER: S-EPMC8095610 | biostudies-literature | 2008 Apr

REPOSITORIES: biostudies-literature

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Up-regulation of adenosine receptors in the frontal cortex in Alzheimer's disease.

Albasanz José L JL Perez Sandra S Barrachina Marta M Ferrer Isidro I Martín Mairena M

Brain pathology (Zurich, Switzerland) 20080129 2

Adenosine receptors are G-protein coupled receptors which modulate neurotransmitter release, mainly glutamate. Adenosine A(1) and A(2A) receptors were studied in post-mortem human cortex in Alzheimer's disease (AD) and age-matched controls. Total adenosine A(1) receptor number, determined by radioligand binding assay, using [(3)H]DPCPX, was significantly increased in AD cases in early and advanced stages without differences with the progression of the disease. A significant increase of A(1)R (37 ...[more]

PMID: 18241242

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Project description:BackgroundAlzheimer's disease (AD) is the sixth leading cause of death and the most costly disease in the US. Despite the enormous impact of AD, there are no treatments that delay onset or stop disease progression currently on the market. This is partly due to the complexity of the disease and the largely unknown pathogenesis of sporadic AD, which accounts for the vast majority of cases. Epigenetics has been implicated as a critical component to AD pathology and a potential "hot spot" for treatments. Histone post-translational modifications (PTMs) are a key element in epigenetic regulation of gene expression and are known to be associated with the pathology of numerous diseases. Investigation of histone PTMs can help elucidate AD pathology and identify targets for therapies.ResultsA multiple reaction monitoring mass spectrometry assay was used to measure changes in abundance of several histone PTMs in frontal cortex from human donors affected with AD (n = 6) and age-matched, normal donors (n = 6). Of the changes observed, notable decreases in methylation of H2B residue K108 by 25 % and H4 residue R55 by 35 % were measured and are likely associated with hydrogen bonding networks important for nucleosome stability. Additionally, a 91 % increase in ubiquitination of K120 on H2B was measured as well as an apparent loss in acetylation of the region near the N-terminus of H4. Our method of quantification was also determined to be precise and robust, signifying measured changes were representative of true biological differences between donors and sample groups.ConclusionWe are the first to report changes in methylation of H2B K108, methylation of H4 R55, and ubiquitination of H2B K120 in frontal cortex from human donors with AD. These notable PTM changes may be of great importance in elucidating the epigenetic mechanism of AD as it relates to disease pathology. Beyond the structural and functional impacts of the changes we have measured, the sites of altered PTMs may be used to identify enzymes responsible for their modulation, which could be used as prospective drug targets for highly specific AD therapies.

Project description:Environmental enrichment (EE) is widely used in the life sciences to study effects of environment on the brain. In pigs, despite lack of EE being a key welfare issue there is little understanding of brain effects of EE in pigs. This project aimed to study the effects of exposure to an EE arena on piglet behaviours and on brain gene expression levels with a focus on IGF-1 and related genes. Eight litters of large white×landrace×Hampshire piglets were farrowed and raised in a free farrowing system (PigSAFE). At 42days of age, 6pigletsperlitter were given access to an enriched arena with plentiful peat, straw and space, (in groups of 4 made up of stable pairs) for 15min per day on 5 consecutive days to allow them to habituate to the apparatus. Piglet behaviours were recorded in the arena for 15min periods on 3 consecutive days. On the final day only one pair of test piglets per litter was given access to the arena. Brain tissue was collected within 45min of the test from piglets exposed to the arena on the day and their non-exposed littermate controls. RNA was extracted from the frontal cortex and QRT-PCR for selected genes run on a Stratgene MX3005P. In both the home pen and the EE arena litters spent the largest proportion of time engaging in foraging behaviour which was significantly increased in the enriched arena (t7=5.35, df=6, p=0.001). There were decreases in non-running play (t7=4.82, p=0.002) and inactivity (t7=4.6, p=0.002) in the arena. A significant fold change increase (FC=1.07, t=4.42, p=0.002) was observed in IGF-1 gene expression in the frontal cortex of piglets exposed to the enriched arena compared to those not exposed on the day of culling. No change in expression was observed in CSF1, the IGF-1 receptor gene nor in any of the binding proteins tested (IGFBP1-6). There was a weak tendency for increased expression of the neurotrophic factor BDNF1 (fold change: 1.03; t7=1.54, p=0.1). We believe this work is the first to explore effects of EE on pig brain physiology and development, and also points to a potential role for IGF-1 in brain effects of EE.

Dataset Information

Up-regulation of adenosine receptors in the frontal cortex in Alzheimer's disease.

Publications

Up-regulation of adenosine receptors in the frontal cortex in Alzheimer's disease.

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