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1.
Glia ; 66(11): 2316-2323, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30098078

RESUMO

Oxidative stress and oxidative DNA damage are early features of mild cognitive impairment and Alzheimer's disease (AD), occurring before the formation of classical AD neuropathology, and resulting from an imbalance between pro- and anti-oxidants. Astrocytes play a major neuroprotective role, producing high levels of anti-oxidants including metallothionein-I and -II (MT-I/II). In the present study we characterized the immunoreactive profile of MT-I/II in the temporal cortex of the Cognitive Function and Ageing Study (CFAS) aging population-representative neuropathology cohort, and examined H2 O2 -modulation of MT transcription by human astrocytes. MT-I/II is primarily expressed by astrocytes in the aging brain, but is also associated with pyramidal neurons in a small proportion of cases. Astrocyte expression of MT-I/II does not correlate with Alzheimer-type pathology (Aß plaques and neurofibrillary tangles) but does relate to astrocyte oxidative DNA damage (rs = .312, p = .006) and the astrocyte response to oxidative DNA damage in vivo (rs = .238, p = .04), and MT gene expression is significantly induced in human astrocytes response to oxidative stress in vitro (p = .01). In contrast, neuronal MT-I/II does not relate to oxidative DNA damage or the neuronal DNA damage response, but is significantly higher in cases with high levels of local tangle pathology (p = .007). As MT-I/II is neuroprotective against oxidative stress, modulation of MT-I/II expression is a potential therapeutic target to treat the onset and progression of cognitive impairment.


Assuntos
Envelhecimento/patologia , Doença de Alzheimer/patologia , Astrócitos/metabolismo , Encéfalo/metabolismo , Dano ao DNA/fisiologia , Metalotioneína/metabolismo , Idoso , Idoso de 80 Anos ou mais , Astrócitos/efeitos dos fármacos , Astrócitos/patologia , Encéfalo/patologia , Células Cultivadas , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Peróxido de Hidrogênio/farmacologia , Masculino , Metalotioneína/genética , Neurônios/metabolismo , Tauopatias/metabolismo , Tauopatias/patologia , Fatores de Tempo
2.
Acta Neuropathol Commun ; 9(1): 5, 2021 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-33407907

RESUMO

Type 2 diabetes mellitus (T2D), characterised by peripheral insulin resistance, is a risk factor for dementia. In addition to its contribution to small and large vessel disease, T2D may directly damage cells of the brain neurovascular unit. In this study, we investigated the transcriptomic changes in cortical neurones, and associated astrocytes and endothelial cells of the neurovascular unit, in the ageing brain. Neurone, astrocyte, and endothelial cell-enriched mRNA, obtained by immuno-laser capture microdissection of temporal cortex (Brodmann area 21/22) from 6 cases with self-reported T2D in the Cognitive Function and Ageing Study neuropathology cohort, and an equal number of age and sex-matched controls, was assessed by microarray analysis. Integrated Molecular Pathway Level Analysis was performed using the Kyoto Encyclopaedia of Genes and Genomes database on significantly differentially expressed genes, defined as P < 0.05 and fold-change ± 1.2. Hub genes identified from Weighted Gene Co-expression Network Analysis were validated in neurones using the NanoString nCounter platform. The expression and cellular localisation of proteins encoded by selected candidate genes were confirmed by immunohistochemistry. 912, 2202, and 1227 genes were significantly differentially expressed between cases with self-reported T2D and controls in neurones, astrocytes, and endothelial cells respectively. Changes in cortical neurones included alterations in insulin and other signalling pathways, cell cycle, cellular senescence, inflammatory mediators, and components of the mitochondrial respiratory electron transport chain. Impaired insulin signalling was shared by neurovascular unit cells with, additionally, apoptotic pathway changes in astrocytes and dysregulation of advanced glycation end-product signalling in endothelial cells. Transcriptomic analysis identified changes in key cellular pathways associated with T2D that may contribute to neuronal damage and dysfunction. These effects on brain cells potentially contribute to a diabetic dementia, and may provide novel approaches for therapeutic intervention.


Assuntos
Envelhecimento/genética , Astrócitos/metabolismo , Diabetes Mellitus Tipo 2/genética , Células Endoteliais/metabolismo , Neurônios/metabolismo , RNA Mensageiro/metabolismo , Lobo Temporal/metabolismo , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/metabolismo , Encéfalo/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Feminino , Humanos , Microdissecção e Captura a Laser , Masculino , Lobo Temporal/citologia , Transcriptoma
3.
J Neuropathol Exp Neurol ; 79(9): 950-958, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32766675

RESUMO

Diabetes mellitus is a risk factor for dementia, and nonenzymatic glycosylation of macromolecules results in formation of advanced glycation end-products (AGEs). We determined the variation in AGE formation in brains from the Cognitive Function and Ageing Study population-representative neuropathology cohort. AGEs were measured on temporal neocortex by enzyme-linked immunosorbent assay (ELISA) and cell-type specific expression on neurons, astrocytes and endothelium was detected by immunohistochemistry and assessed semiquantitatively. Fifteen percent of the cohort had self-reported diabetes, which was not significantly associated with dementia status at death or neuropathology measures. AGEs were expressed on neurons, astrocytes and endothelium and overall expression showed a positively skewed distribution in the population. AGE measures were not significantly associated with dementia. AGE measured by ELISA increased with Consortium to Establish a Registry for Alzheimer's Disease (CERAD) neurofibrillary tangle score (p = 0.03) and Thal Aß phase (p = 0.04), while AGE expression on neurons (and astrocytes), detected immunohistochemically, increased with increasing Braak tangle stage (p < 0.001), CERAD tangle score (p = 0.002), and neuritic plaques (p = 0.01). Measures of AGE did not show significant associations with cerebral amyloid angiopathy, microinfarcts or neuroinflammation. In conclusion, AGE expression increases with Alzheimer's neuropathology, particular later stages but is not independently associated with dementia. AGE formation is likely to be important for impaired brain cell function in aging and Alzheimer's.


Assuntos
Envelhecimento/metabolismo , Envelhecimento/patologia , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Produtos Finais de Glicação Avançada/metabolismo , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Estudos de Coortes , Demência/metabolismo , Demência/patologia , Feminino , Humanos , Masculino , Emaranhados Neurofibrilares/metabolismo , Emaranhados Neurofibrilares/patologia , Placa Amiloide/metabolismo , Placa Amiloide/patologia
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