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1.
Hum Brain Mapp ; 2019 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-31765057

RESUMO

Executive function (EF) is a set of cognitive capabilities considered essential for successful daily living, and is negatively affected by ageing and neurodegenerative conditions. Underpinning EF performance are functional nodes in the executive control network (ECN), while the structural connectivity underlying this network is not well understood. In this paper, we evaluated the structural white matter tracts that interconnect the ECN and investigated their relationship to the EF performance. Using high-angular resolution diffusion MRI data, we performed tractography analysis of structural connectivity in a cognitively normal cohort (n = 140), specifically targeting the connectivity between ECN nodes. Our data revealed the presence of a strongly-connected "structural core" of the ECN comprising three components: interhemispheric frontal connections, a fronto-parietal subnetwork and fronto-striatal connections between right dorsolateral prefrontal cortex and right caudate. These pathways were strongly correlated with EF performance (p = .003). Post-hoc analysis of subregions within the significant ECN connections showed that these effects were driven by a highly specific subset of interconnected cortical regions. The structural core subnetwork of the functional ECN may be an important feature crucial to a better future understanding of human cognition and behaviour.

2.
J Biol Chem ; 294(38): 14149-14162, 2019 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-31366728

RESUMO

The microtubule-associated protein tau undergoes aberrant modification resulting in insoluble brain deposits in various neurodegenerative diseases, including frontotemporal dementia (FTD), progressive supranuclear palsy, and corticobasal degeneration. Tau aggregates can form in different cell types of the central nervous system (CNS) but are most prevalent in neurons. We have previously recapitulated aspects of human FTD in mouse models by overexpressing mutant human tau in CNS neurons, including a P301S tau variant in TAU58/2 mice, characterized by early-onset and progressive behavioral deficits and FTD-like neuropathology. The molecular mechanisms underlying the functional deficits of TAU58/2 mice remain mostly elusive. Here, we employed functional genomics (i.e. RNAseq) to determine differentially expressed genes in young and aged TAU58/2 mice to identify alterations in cellular processes that may contribute to neuropathy. We identified genes in cortical brain samples differentially regulated between young and old TAU58/2 mice relative to nontransgenic littermates and by comparative analysis with a dataset of CNS cell type-specific genes expressed in nontransgenic mice. Most differentially-regulated genes had known or putative roles in neurons and included presynaptic and excitatory genes. Specifically, we observed changes in presynaptic factors, glutamatergic signaling, and protein scaffolding. Moreover, in the aged mice, expression levels of several genes whose expression was annotated to occur in other brain cell types were altered. Immunoblotting and immunostaining of brain samples from the TAU58/2 mice confirmed altered expression and localization of identified and network-linked proteins. Our results have revealed genes dysregulated by progressive tau accumulation in an FTD mouse model.

3.
Curr Protoc Mol Biol ; 126(1): e86, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30735313

RESUMO

Matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI-IMS) is a well-established technique for elucidating the location and relative abundance of a range of biomolecules. More recently, research into this technique has shifted from simple discovery and demonstration of utility to application in biomedical research. Here, we describe a protocol utilizing MALDI-IMS for the spatial mapping of lipids in brain tissue from normal human brains and brains from patients with Alzheimer's disease, in the context of Alzheimer's disease. Improved accuracy calibration of the instrument from the tissue surface is emphasized, as this allows for significantly improved mass determination in time of flight (TOF)-based instruments enabling more confident preliminary lipid identification. This improved initial result allows MALDI-IMS data to be complemented with additional instrumentation, such as liquid chromatography mass spectrometry workflows or specialized non-TOF systems such as Fourier transform cyclotron resonance instruments. This method is not limited to human tissue and can be applied to virtually any lipid-rich formalin-fixed tissue. © 2019 by John Wiley & Sons, Inc.


Assuntos
Doença de Alzheimer/patologia , Química Encefálica , Encéfalo/patologia , Lipídeos/análise , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Humanos
4.
Front Neurosci ; 12: 533, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30150923

RESUMO

The overwhelming majority of dominant mutations causing early onset familial Alzheimer's disease (EOfAD) occur in only three genes, PSEN1, PSEN2, and APP. An effect-in-common of these mutations is alteration of production of the APP-derived peptide, amyloid ß (Aß). It is this key fact that underlies the authority of the Amyloid Hypothesis that has informed Alzheimer's disease research for over two decades. Any challenge to this authority must offer an alternative explanation for the relationship between the PSEN genes and APP. In this paper, we explore one possible alternative relationship - the dysregulation of cellular iron homeostasis as a common effect of EOfAD mutations in these genes. This idea is attractive since it provides clear connections between EOfAD mutations and major characteristics of Alzheimer's disease such as dysfunctional mitochondria, vascular risk factors/hypoxia, energy metabolism, and inflammation. We combine our ideas with observations by others to describe a "Stress Threshold Change of State" model of Alzheimer's disease that may begin to explain the existence of both EOfAD and late onset sporadic (LOsAD) forms of the disease. Directing research to investigate the role of dysregulation of iron homeostasis in EOfAD may be a profitable way forward in our struggle to understand this form of dementia.

5.
Sci Rep ; 8(1): 11553, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-30068908

RESUMO

The pathogenesis of Alzheimer's disease (AD) remains to be elucidated. Oxidative damage and excessive beta-amyloid oligomers are components of disease progression but it is unclear how these factors are temporally related. At post mortem, the superior temporal gyrus (STG) of AD cases contains plaques, but displays few tangles and only moderate neuronal loss. The STG at post mortem may represent a brain region that is in the early stages of AD or alternately a region resistant to AD pathogenesis. We evaluated expression profiles and activity of endogenous anti-oxidants, oxidative damage and caspase activity in the STG of apolipoprotein ε4-matched human AD cases and controls. Total superoxide dismutase (SOD) activity was increased, whereas total glutathione peroxidase (GPX), catalase (CAT) and peroxiredoxin (Prx) activities, were decreased in the AD-STG, suggesting that hydrogen peroxide accumulates in this brain region. Transcripts of the transcription factor NFE2L2 and inducible HMOX1, were also increased in the AD-STG, and this corresponded to increased Nuclear factor erythroid 2-related factor (NRF-2) and total heme-oxygenase (HO) activity. The protein oxidation marker 4-hydroxynonenal (4-HNE), remained unchanged in the AD-STG. Similarly, caspase activity was unaltered, suggesting that subtle redox imbalances in early to moderate stages of AD do not impact STG viability.


Assuntos
Doença de Alzheimer/patologia , Doença de Alzheimer/fisiopatologia , Estresse Oxidativo , Lobo Temporal/patologia , Antioxidantes/análise , Caspases/análise , Feminino , Perfilação da Expressão Gênica , Humanos , Masculino
6.
Alcohol ; 67: 51-63, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29425959

RESUMO

BACKGROUND: Chronic alcohol use disorders (AUD) are associated with white matter (WM) degeneration with altered myelin integrity. Matrix assisted laser desorption ionization-imaging mass spectrometry (MALDI-IMS) enables high throughput analysis of myelin lipid biochemical histopathology to help characterize disease mechanisms. PURPOSE: This study utilized MALDI-IMS to investigate frontal lobe WM myelin lipid abnormalities in AUD. METHODS: Standardized cores of formalin-fixed WM from Brodmann Area 4 (BA4) and BA8/9 of 20 postmortem AUD and 19 control adult human brains were embedded in carboxymethyl-cellulose, cryo-sectioned (8 µm), thaw-mounted onto indium tin oxide (ITO) -coated glass slides, and sublimed with 2,5-dihydroxybenzxoic acid (DHB) matrix. Lipids were imaged by MALDI-time of flight in the negative ionization mode. Data were visualized with FlexImaging software v4.0 and analyzed with ClinProTools v3.0. RESULTS: Principal component analysis (PCA) and data bar plots of MALDI-IMS data differentiated AUD from control WM. The dominant effect of AUD was to broadly reduce expression of sphingolipids (sulfatides and ceramides) and phospholipids. Data bar plots demonstrated overall similar responses to AUD in BA4 and BA8/9. However, differential regional effects of AUD on WM lipid profiles were manifested by non-overlapping expression or discordant responses to AUD for a subset of lipid ions. CONCLUSIONS: Human AUD is associated with substantial inhibition of frontal lobe WM lipid expression with regional variability in these effects. MALDI-IMS can be used to characterize the nature of AUD-associated lipid biochemical abnormalities for correlation with lifetime exposures and WM degeneration, altered gene expression, and responses to abstinence or treatment.


Assuntos
Alcoolismo/metabolismo , Lobo Frontal/metabolismo , Fosfolipídeos/metabolismo , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Esfingolipídeos/metabolismo , Substância Branca/metabolismo , Adulto , Idoso , Alcoólicos , Alcoolismo/patologia , Feminino , Lobo Frontal/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Componente Principal/métodos , Substância Branca/patologia
7.
J Alzheimers Dis ; 59(2): 393-403, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28372332

RESUMO

Diabetes and dementia are two diseases that increased dramatically in most societies in direct proportion to increases in average life expectancy. The two conditions are strongly associated and there is much hope that understanding this association will unlock the enigma that is the pathogenesis of dementia. Previous studies suggest that type 2 diabetes is a risk factor for all-cause dementia, vascular dementia and Alzheimer's disease. However these estimates may not necessarily have taken into account the overlap in dementia pathologies or the competing risk of death. Although the link between diabetes and vascular disease is intuitive, it is now becoming clear that type 2 diabetes is also associated with reduced brain volumes and with progression of brain atrophy, apparently independent of its relation with cerebrovascular disease. This raises the possibility that type 2 diabetes may also contribute to neurodegeneration, and particularly tau pathology. Prospective studies that record extensive multimodal in-vivo biomarkers and conduct rigorous postmortem neuropathological examination are certainly required to tease apart these complex pathways. However monitoring cognitive outcomes from current observational studies and randomized clinical trials of new diabetes treatments could be equally valuable in reducing the dementia epidemic.


Assuntos
Demência/epidemiologia , Diabetes Mellitus Tipo 2/epidemiologia , Demência/patologia , Diabetes Mellitus Tipo 2/patologia , Humanos , Fatores de Risco
8.
Metab Brain Dis ; 31(3): 497-515, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26883429

RESUMO

The prevalence of both diabetes and Alzheimer's disease (AD) are reaching epidemic proportions worldwide. Alarmingly, diabetes is also a risk factor for Alzheimer's disease. The AD brain is characterised by the accumulation of peptides called Aß as plaques in the neuropil and hyperphosphorylated tau protein in the form of neurofibrillary tangles within neurons. How diabetes confers risk is unknown but a simple linear relationship has been proposed whereby the hyperinsulinemia associated with type 2 diabetes leads to decreased insulin signaling in the brain, with downregulation of the PI3K/AKT signalling pathway and its inhibition of the major tau kinase, glycogen synthase kinase 3ß. The earliest studies of post mortem AD brain tissue largely confirmed this cascade of events but subsequent studies have generally found either an upregulation of AKT activity, or that the relationship between insulin signaling and AD is independent of glycogen synthase kinase 3ß altogether. Given the lack of success of beta-amyloid-reducing therapies in clinical trials, there is intense interest in finding alternative or adjunctive therapeutic targets for AD. Insulin signaling is a neuroprotective pathway and represents an attractive therapeutic option. However, this incredibly complex signaling pathway is not fully understood in the human brain and particularly in the context of AD. Here, we review the ups and downs of the research efforts aimed at understanding how diabetes modifies AD risk.


Assuntos
Doença de Alzheimer/metabolismo , Encéfalo/patologia , Diabetes Mellitus Tipo 2/metabolismo , Insulina/metabolismo , Receptor de Insulina/metabolismo , Encéfalo/metabolismo , Quinase 3 da Glicogênio Sintase/metabolismo , Humanos , Neurônios/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de Sinais/fisiologia
9.
Neuropathol Appl Neurobiol ; 41(7): 906-25, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25763777

RESUMO

AIM: Tau becomes hyperphosphorylated in Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD-tau), resulting in functional deficits of neurones, neurofibrillary tangle (NFT) formation and eventually dementia. Expression of mutant human tau in the brains of transgenic mice has produced different lines that recapitulate various aspects of FTLD-tau and AD. In this study, we characterized the novel P301S mutant tau transgenic mouse line, TAU58/2. METHODS: Both young and aged TAU58/2 mice underwent extensive motor testing, after which brain tissue was analysed with immunohistochemistry, silver staining, electron microscopy and Western blotting. Tissue from various FTLD subtypes and AD patients was also analysed for comparison. RESULTS: TAU58/2 mice presented with early-onset motor deficits, which became more pronounced with age. Throughout the brains of these mice, tau was progressively hyperphosphorylated resulting in increased NFT formation with age. In addition, frequent axonal swellings that stained intensively for neurofilament (NF) were present in young TAU58/2 mice prior to NFT formation. Similar axonal pathology was also observed in human FTLD-tau and AD. Interestingly, activated microglia were found in close proximity to neurones harbouring transgenic tau, but were not associated with NF-positive axonal swellings. CONCLUSIONS: In TAU58/2 mice, early tau pathology induces functional deficits of neurones associated with NF pathology. This appears to be specific to tau, as similar changes are observed in FTLD-tau, but not in FTLD with TDP-43 inclusions. Therefore, TAU58/2 mice recapitulate aspects of human FTLD-tau and AD pathology, and will become instrumental in studying disease mechanisms and therapeutics in the future.


Assuntos
Axônios/patologia , Encéfalo/patologia , Degeneração Lobar Frontotemporal/patologia , Neurônios/patologia , Animais , Encéfalo/metabolismo , Modelos Animais de Doenças , Degeneração Lobar Frontotemporal/genética , Degeneração Lobar Frontotemporal/metabolismo , Camundongos , Camundongos Transgênicos , Neurônios/metabolismo , Proteínas tau/genética , Proteínas tau/metabolismo
10.
Handb Clin Neurol ; 125: 603-15, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25307599

RESUMO

Chronic alcohol consumption results in structural changes to the brain. In alcoholics without coexisting thiamine deficiency or liver disease this is largely restricted to a loss of white-matter volume. When it occurs, neuronal loss is limited in anatomic distribution and only detected with quantitative techniques. This relative paucity of neurodegeneration is reflected in studies of gene and protein expression in postmortem brain where findings are subtle and discordant between studies. In alcoholics with coexisting pathologies, neuronal loss is more marked and affects a wider range of anatomic regions, especially subcortical nuclei. Although this more widespread damage may reflect a more severe drinking history, there is evidence linking thiamine deficiency and the consequences of liver disease to the pathogenesis of alcohol-related brain damage. Furthermore, a range of other factors, such as cigarette smoking and mood disorders, that are common in alcoholics, have the potential to influence studies of brain pathology and should be considered in further studies of the neuropathology of alcoholism.


Assuntos
Alcoolismo/patologia , Encéfalo/patologia , Alcoolismo/genética , Alcoolismo/metabolismo , Animais , Encéfalo/metabolismo , Humanos , Deficiência de Tiamina/genética , Deficiência de Tiamina/metabolismo , Deficiência de Tiamina/patologia , Encefalopatia de Wernicke/genética , Encefalopatia de Wernicke/metabolismo , Encefalopatia de Wernicke/patologia
11.
Mol Biol Rep ; 41(10): 6365-76, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24996286

RESUMO

The prevalence of Alzheimer's disease (AD) is increasing rapidly worldwide due to an ageing population and a lack of disease modifying therapeutics. In monogenic forms of AD mutations lead to the accumulation of neurotoxic peptides called beta-amyloid. Beta-amyloid accumulation is also postulated to precipitate sporadic AD although the pathogenesis of this common form remains largely unknown. The two leading risk factors for sporadic AD are ageing and the possession of the APOE epsilon 4 allele. Changes in APOE expression that are independent of the epsilon genotype have also been described in the AD brain including a recent RNA-Seq analysis that showed upregulation of a rare alternative splice isoform (APOE-005). To replicate these RNA-Seq findings we used quantitative reverse transcriptase polymerase chain reaction (RT-qPCR) to compare APOE-005 and total APOE expression in the superior temporal gyrus of 14 AD cases and 16 neurologically normal controls. In AD, this area shows prominent beta-amyloid deposition but few neurofibrillary tangles and only moderate neuronal loss. As poorer RNA quality among the AD cases was a likely confounder in this study, the analysis was repeated in a RIN-matched sub-cohort of 17 individuals. Contrary to the original RNA-Seq study, we found no difference in total APOE, APOE-005 or the common isoform, APOE-001, between AD cases and controls. Our findings are consistent with ApoE acting largely at the protein level to increase the risk for sporadic AD.


Assuntos
Processamento Alternativo , Doença de Alzheimer/genética , Apolipoproteínas E/genética , Encéfalo/metabolismo , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/patologia , Estudos de Casos e Controles , Feminino , Expressão Gênica , Regulação da Expressão Gênica , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Estabilidade de RNA , Transcrição Genética
13.
Alcohol Clin Exp Res ; 38(4): 994-1001, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24460866

RESUMO

BACKGROUND: Alcohol abuse is the world's third leading cause of disease and disability, and one potential sequel of chronic abuse is alcohol-related brain damage (ARBD). This clinically manifests as cognitive dysfunction and pathologically as atrophy of white matter (WM) in particular. The mechanism linking chronic alcohol intoxication with ARBD remains largely unknown but it is also complicated by common comorbidities such as liver damage and nutritional deficiencies. Liver cirrhosis, in particular, often leads to hepatic encephalopathy (HE), a primary glial disease. METHODS: In a novel transcriptomic study, we targeted the WM only of chronic alcoholics in an attempt to tease apart the pathogenesis of ARBD. Specifically, in alcoholics with and without HE, we explored both the prefrontal and primary motor cortices, 2 regions that experience differential levels of neuronal loss. RESULTS: Our results suggest that HE, along with 2 confounders, gray matter contamination, and low RNA quality are major drivers of gene expression in ARBD. All 3 exceeded the effects of alcohol itself. In particular, low-quality RNA samples were characterized by an up-regulation of translation machinery, while HE was associated with a down-regulation of mitochondrial energy metabolism pathways. CONCLUSIONS: The findings in HE alcoholics are consistent with the metabolic acidosis seen in this condition. In contrast non-HE alcoholics had widespread but only subtle changes in gene expression in their WM. Notwithstanding the latter result, this study demonstrates that significant confounders in transcriptomic studies of human postmortem brain tissue can be identified, quantified, and "removed" to reveal disease-specific signals.


Assuntos
Alcoolismo/genética , Alcoolismo/metabolismo , Transcriptoma/fisiologia , Substância Branca/metabolismo , Idoso , Idoso de 80 Anos ou mais , Alcoolismo/epidemiologia , Estudos de Coortes , Comorbidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
14.
Alcohol Clin Exp Res ; 38(1): 1-8, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24033426

RESUMO

The New South Wales Tissue Resource Centre at the University of Sydney, Australia, is one of the few human brain banks dedicated to the study of the effects of chronic alcoholism. The bank was affiliated in 1994 as a member of the National Network of Brain Banks and also focuses on schizophrenia and healthy control tissue. Alcohol abuse is a major problem worldwide, manifesting in such conditions as fetal alcohol syndrome, adolescent binge drinking, alcohol dependency, and alcoholic neurodegeneration. The latter is also referred to as alcohol-related brain damage (ARBD). The study of postmortem brain tissue is ideally suited to determining the effects of long-term alcohol abuse, but it also makes an important contribution to understanding pathogenesis across the spectrum of alcohol misuse disorders and potentially other neurodegenerative diseases. Tissue from the bank has contributed to 330 peer-reviewed journal articles including 120 related to alcohol research. Using the results of these articles, this review chronicles advances in alcohol-related brain research since 2003, the so-called genomic age. In particular, it concentrates on transcriptomic approaches to the pathogenesis of ARBD and builds on earlier reviews of structural changes (Harper et al. Prog Neuropsychopharmacol Biol Psychiatry 2003;27:951) and proteomics (Matsumoto et al. Expert Rev Proteomics 2007;4:539).


Assuntos
Alcoolismo/diagnóstico , Alcoolismo/genética , Encéfalo/patologia , Genômica/métodos , Alcoolismo/epidemiologia , Austrália/epidemiologia , Autopsia , Humanos , Neurogênese/fisiologia , Bancos de Tecidos , Transcriptoma/genética
15.
Metab Brain Dis ; 29(4): 1027-39, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24346482

RESUMO

Hepatic encephalopathy (HE) is a common complication of chronic alcoholism and patients show neurological symptoms ranging from mild cognitive dysfunction to coma and death. The HE brain is characterized by glial changes, including microglial activation, but the exact pathogenesis of HE is poorly understood. During a study investigating cell proliferation in the subventricular zone of chronic alcoholics, a single case with widespread proliferation throughout their adjacent grey and white matter was noted. This case also had concomitant HE raising the possibility that glial proliferation might be a pathological feature of the disease. In order to explore this possibility fixed postmortem human brain tissue from chronic alcoholics with cirrhosis and HE (n = 9), alcoholics without HE (n = 4) and controls (n = 4) were examined using immunohistochemistry and cytokine assays. In total, 4/9 HE cases had PCNA- and a second proliferative marker, Ki-67-positive cells throughout their brain and these cells co-stained with the microglial marker, Iba1. These cases were termed 'proliferative HE' (pHE). The microglia in pHEs displayed an activated morphology with hypertrophied cell bodies and short, thickened processes. In contrast, the microglia in white matter regions of the non-proliferative HE cases were less activated and appeared dystrophic. pHEs were also characterized by higher interleukin-6 levels and a slightly higher neuronal density . These findings suggest that microglial proliferation may form part of an early neuroprotective response in HE that ultimately fails to halt the course of the disease because underlying etiological factors such as high cerebral ammonia and systemic inflammation remain.


Assuntos
Alcoolismo/patologia , Encéfalo/patologia , Encefalopatia Hepática/patologia , Microglia/patologia , Alcoolismo/complicações , Química Encefálica , Contagem de Células , Divisão Celular , Citocinas/análise , Feminino , Encefalopatia Hepática/etiologia , Humanos , Hipertrofia , Antígeno Ki-67/análise , Cirrose Hepática Alcoólica/patologia , Masculino , Pessoa de Meia-Idade , Neurônios/patologia , Antígeno Nuclear de Célula em Proliferação/análise , Fumar/patologia , Substância Branca/patologia
16.
Redox Rep ; 18(4): 134-41, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23849337

RESUMO

The prevalence of Alzheimer's disease (AD) is increasing rapidly worldwide due to an ageing population and largely ineffective treatments. In AD cognitive decline is due to progressive neuron loss that begins in the medial temporal lobe and spreads through many brain regions. Despite intense research the pathogenesis of the common sporadic form of AD remains largely unknown. The popular amyloid cascade hypothesis suggests that the accumulation of soluble oligomers of beta amyloid peptides (Aß) initiates a series of events that cause neuronal loss. Among their putative toxic effects, Aß oligomers are thought to act as pro-oxidants combining with redox-active metals to produce excessive reactive oxygen and nitrogen species. However, to date the experimental therapies that reduce Aß load in AD have failed to halt cognitive decline. Another hypothesis proposed by the late Mark Smith and colleagues is that oxidative stress, rather than Aß, precipitates the pathogenesis of AD. That is, Aß and microtubule-associated protein tau are upregulated to address the redox imbalance in the AD brain. As the disease progresses, excess Aß and tau oligomerise to further accelerate the disease process. Here, we discuss redox balance in the human brain and how this balance is affected by ageing. We then discuss where oxidative stress is most likely to act in the disease process and the potential for intervention to reduce its effects.


Assuntos
Doença de Alzheimer/etiologia , Estresse Oxidativo , Idoso , Envelhecimento/fisiologia , Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides/biossíntese , Antioxidantes/fisiologia , Humanos , Radical Hidroxila/metabolismo , Modelos Biológicos , Neurônios/patologia , Oxirredução , Espécies Reativas de Oxigênio/metabolismo , Regulação para Cima , Proteínas tau/biossíntese
17.
Parkinsonism Relat Disord ; 18(4): 351-7, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22172551

RESUMO

Genes involved in familial dystonia syndromes (DYT genes) are ideal candidates for investigating whether common genetic variants influence the susceptibility to sporadic primary dystonia. To date, there have been few candidate gene studies for primary dystonia and only two DYT genes, TOR1A and THAP1, have been assessed. We therefore employed a haplotype-tagging strategy to comprehensively assess if common polymorphisms in eight DYT genes (TOR1A, TAF1, GCH1, THAP1, MR-1 (PNKD), SGCE, ATP1A3 and PRKRA) confer risk for sporadic primary dystonia. The 230 primary dystonia cases were matched for age and gender to 228 controls, recruited from movement disorder clinics in Brisbane, Australia and the Australian electoral roll. All subjects were genotyped for 56 tagging SNPs and genotype associations were investigated. Modest genotypic associations (P<0.05) were observed for three GCH1 SNPs (rs12147422, rs3759664 and rs10483639) when comparing all cases against controls. Associations were also seen when the cases were stratified based on presentation. Overall, our findings do not support the hypothesis that common TOR1A variants affect susceptibility for sporadic primary dystonia, and that it is unlikely that common variants around the DYT genes confer substantial risk for sporadic primary dystonia. Further work is warranted to follow up the GCH1 SNPs and the subgroup analyses.


Assuntos
Distúrbios Distônicos/genética , GTP Cicloidrolase/genética , Predisposição Genética para Doença/genética , Chaperonas Moleculares/genética , Polimorfismo de Nucleotídeo Único , Idoso , Austrália , Estudos de Casos e Controles , Feminino , Frequência do Gene , Estudos de Associação Genética , Genótipo , Humanos , Masculino , Metanálise como Assunto , Pessoa de Meia-Idade
18.
PLoS One ; 6(7): e21907, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21747966

RESUMO

BACKGROUND: Without appropriate cellular models the etiology of idiopathic Parkinson's disease remains unknown. We recently reported a novel patient-derived cellular model generated from biopsies of the olfactory mucosa (termed olfactory neurosphere-derived (hONS) cells) which express functional and genetic differences in a disease-specific manner. Transcriptomic analysis of Patient and Control hONS cells identified the NRF2 transcription factor signalling pathway as the most differentially expressed in Parkinson's disease. RESULTS: We tested the robustness of our initial findings by including additional cell lines and confirmed that hONS cells from Patients had 20% reductions in reduced glutathione levels and MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt] metabolism compared to cultures from healthy Control donors. We also confirmed that Patient hONS cells are in a state of oxidative stress due to higher production of H(2)O(2) than Control cultures. siRNA-mediated ablation of NRF2 in Control donor cells decreased both total glutathione content and MTS metabolism to levels detected in cells from Parkinson's Disease patients. Conversely, and more importantly, we showed that activation of the NRF2 pathway in Parkinson's disease hONS cultures restored glutathione levels and MTS metabolism to Control levels. Paradoxically, transcriptomic analysis after NRF2 pathway activation revealed an increased number of differentially expressed mRNAs within the NRF2 pathway in L-SUL treated Patient-derived hONS cells compared to L-SUL treated Controls, even though their metabolism was restored to normal. We also identified differential expression of the PI3K/AKT signalling pathway, but only post-treatment. CONCLUSIONS: Our results confirmed NRF2 as a potential therapeutic target for Parkinson's disease and provided the first demonstration that NRF2 function was inducible in Patient-derived cells from donors with uniquely varied genetic backgrounds. However, our results also demonstrated that the response of PD patient-derived cells was not co-ordinated in the same way as in Control cells. This may be an important factor when developing new therapeutics.


Assuntos
Fator 2 Relacionado a NF-E2/metabolismo , Mucosa Olfatória/metabolismo , Mucosa Olfatória/patologia , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Estudos de Casos e Controles , Linhagem Celular , Feminino , Inativação Gênica , Glutationa/metabolismo , Humanos , Isotiocianatos , Masculino , Fator 2 Relacionado a NF-E2/deficiência , Fator 2 Relacionado a NF-E2/genética , Mucosa Olfatória/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Sais de Tetrazólio/metabolismo , Tiazóis/metabolismo , Tiocianatos/farmacologia
19.
J Alzheimers Dis ; 25(3): 395-415, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21441655

RESUMO

Alzheimer's disease (AD) and Parkinson's disease (PD) are the two most common neurodegenerative disorders. Why some individuals develop one disease rather than the other is not clear. Association studies with a case-control design are the time-honored approach to identifying risk factors. Extensive association studies have been carried out in both diseases creating a large knowledge database, however, reproducible risk factors remain rare. This general lack of knowledge of pathogenesis prevents us from reducing the worldwide burden of these diseases. Case-control studies are reductionist paradigms that assume, for maximum power, that the two populations being compared are exclusive and homogenous. The common occurrence of incidental AD and PD-type pathology combined with 'intermediate phenotypes' such as dementia with Lewy bodies suggest that aging itself, AD, and PD are part of a complex continuum characterized by variable amounts of amyloid-ß, tau, and α-synuclein pathology. This heterogeneity may be a contributor to the lack of reproducibility in association studies to date. Here, we speculate on alternative experimental approaches to the case-control paradigm and consider how the association-study literature for AD and PD might be re-interpreted in terms of a disease spectrum.


Assuntos
Doença de Alzheimer/patologia , Conhecimento , Doença de Parkinson/etiologia , Doença de Parkinson/patologia , Fatores Etários , Doenças Cardiovasculares/complicações , Humanos , Modelos Biológicos , Praguicidas/toxicidade , Fenótipo , Fatores de Risco , Fatores Sexuais , Fumar
20.
J Neurochem ; 116(6): 937-46, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21175619

RESUMO

The prevalence of Alzheimer's disease (AD) is increasing rapidly in the western world and is poised to have a significant economic and societal impact. Current treatments do not alter the underlying disease processes meaning new treatments are required if this imminent epidemic is to be averted. The clinical manifestations of AD are secondary to a substantial loss of cortical neurons. To be effective, neuroprotective strategies will need to be implemented prior to this cell loss. However, this requires the discovery of both pre-clinical markers to identify susceptible patients and the early pathogenic mechanisms to serve as therapeutic targets. Although the biomarkers and pathogenic mechanisms may overlap, it is likely that new approaches are required to identify novel elements of the disease. Transcriptomic analyses, that assume no a priori etiological hypotheses, promise much in elucidating the pathogenesis of complex diseases like AD. Microarrays are the most popular platform for transcriptomic analysis and have been applied across AD models, patient samples and postmortem brain tissue. The results of these studies have been largely discordant which could, to some extent, reflect the limitations of this probe-hybridization-based methodology. In comparison, whole transcriptome sequencing (RNA-Seq) utilizes a highly efficient, next-generation DNA sequencing method with improved dynamic range and scope of transcript detection. RNA-Seq is not only highly suited to investigations of the genomically complex human brain tissue but it can potentially overcome technical issues inherent to case-control comparisons of postmortem brain tissue in neurodegenerative diseases. The volume of data generated by this platform looms as the major logistical hurdle and a systematic experimental approach will be required to maximise the detection of pathogenically relevant signals. Nevertheless, RNA-Seq looks set to deliver a quantum leap forward in our understanding of AD pathogenesis.


Assuntos
Doença de Alzheimer/patologia , Perfilação da Expressão Gênica , RNA/análise , Doença de Alzheimer/epidemiologia , Doença de Alzheimer/etiologia , Doença de Alzheimer/genética , Encéfalo/metabolismo , Encéfalo/patologia , Humanos , Cinesina/genética , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Análise de Sequência/métodos
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