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This work aims to clarify the effect of dietary polyunsaturated fatty acid (PUFA) intake on the adult brain affected by amyloid pathology. McGill-R-Thy1-APP transgenic (Tg) rat and 5xFAD Tg mouse models that represent earlier or later disease stages were employed. The animals were exposed to a control diet (CD) or an HFD based on corn oil, from young (rats) or adult (mice) ages for 24 or 10 weeks, respectively. In rats and mice, the HFD impaired reference memory in wild-type (WT) animals but did not worsen it in Tg, did not cause obesity, and did not increase triglycerides or glucose levels. Conversely, the HFD promoted stronger microglial activation in Tg vs. WT rats but had no effect on cerebral amyloid deposition. IFN-γ, IL-1ß, and IL-6 plasma levels were increased in Tg rats, regardless of diet, while CXCL1 chemokine levels were increased in HFD-fed mice, regardless of genotype. Hippocampal 3-nitrotyrosine levels tended to increase in HFD-fed Tg rats but not in mice. Overall, an HFD with an elevated omega-6-to-omega-3 ratio as compared to the CD (25:1 vs. 8.4:1) did not aggravate the outcome of AD regardless of the stage of amyloid pathology, suggesting that many neurobiological processes relevant to AD are not directly dependent on PUFA intake.
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Doença de Alzheimer , Ácidos Graxos Ômega-3 , Camundongos , Ratos , Animais , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Encéfalo/patologia , Camundongos Transgênicos , Amiloide , Modelos Animais de Doenças , Ratos Transgênicos , Dieta HiperlipídicaRESUMO
Interest in the role of melanin-concentrating hormone (MCH) in memory processes has increased in recent years, with some studies reporting memory-enhancing effects, while others report deleterious effects. Due to these discrepancies, this study seeks to provide new evidence about the role of MCH in memory consolidation and its relation with BDNF/TrkB system. To this end, in the first experiment, increased doses of MCH were acutely administered in both hippocampi to groups of male rats (25, 50, 200, and 500 ng). Microinjections were carried out immediately after finishing the sample trial of two hippocampal-dependent behavioral tasks: the Novel Object Recognition Test (NORT) and the modified Elevated Plus Maze (mEPM) test. Results indicated that a dose of 200 ng of MCH or higher impaired memory consolidation in both tasks. A second experiment was performed in which a dose of 200 ng of MCH was administered alone or co-administered with the MCHR-1 antagonist ATC-0175 at the end of the sample trial in the NORT. Results showed that MCH impaired memory consolidation, while the co-administration with ATC-0175 reverted this detrimental effect. Moreover, MCH induced a significant decrease in hippocampal MCHR-1 and TrkB expression with no modification in the expression of BDNF and NMDA receptor subunits NR1, NR2A, and NR2B. These results suggest that MCH in vivo elicits pro-amnesic effects in the rat hippocampus by decreasing the availability of its receptor and TrkB receptors, thus linking both endogenous systems to memory processes.
Assuntos
Fator Neurotrófico Derivado do Encéfalo , Consolidação da Memória , Hormônios Hipofisários , Receptor trkB , Receptores de Somatomedina , Animais , Masculino , Ratos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Melaninas , Hormônios Hipofisários/metabolismo , Receptor trkB/metabolismo , Receptores de Somatomedina/metabolismoRESUMO
Introduction: The metabolic routes altered in Alzheimer's disease (AD) brain are poorly understood. As the metabolic pathways are evolutionarily conserved, the metabolic profiles carried out in animal models of AD could be directly translated into human studies. Methods: We performed untargeted Nuclear Magnetic Resonance metabolomics in hippocampus of McGill-R-Thy1-APP transgenic (Tg) rats, a model of AD-like cerebral amyloidosis and the translational potential of these findings was assessed by targeted Gas Chromatography-Electron Impact-Mass Spectrometry in plasma of participants in the German longitudinal cohort AgeCoDe. Results: In rat hippocampus 26 metabolites were identified. Of these 26 metabolites, nine showed differences between rat genotypes that were nominally significant. Two of them presented partial least square-discriminant analysis (PLS-DA) loadings with the larger absolute weights and the highest Variable Importance in Projection (VIP) scores and were specifically assigned to nicotinamide adenine dinucleotide (NAD) and nicotinamide (Nam). NAD levels were significantly decreased in Tg rat brains as compared to controls. In agreement with these results, plasma of AD patients showed significantly reduced levels of Nam in respect to cognitively normal participants. In addition, high plasma levels of Nam showed a 27% risk reduction of progressing to AD dementia within the following 2.5 years, this hazard ratio is lost afterwards. Discussion: To our knowledge, this is the first report showing that a decrease of Nam plasma levels is observed couple of years before conversion to AD, thereby suggesting its potential use as biomarker for AD progression.
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Several studies suggest that the assembly of mitochondrial respiratory complexes into structures known as supercomplexes (SCs) may increase the efficiency of the electron transport chain, reducing the rate of production of reactive oxygen species. Therefore, the study of the (dis)assembly of SCs may be relevant for the understanding of mitochondrial dysfunction reported in brain aging and major neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD). Here we briefly reviewed the biogenesis and structural properties of SCs, the impact of mtDNA mutations and mitochondrial dynamics on SCs assembly, the role of lipids on stabilization of SCs and the methodological limitations for the study of SCs. More specifically, we summarized what is known about mitochondrial dysfunction and SCs organization and activity in aging, AD and PD. We focused on the critical variables to take into account when postmortem tissues are used to study the (dis)assembly of SCs. Since few works have been performed to study SCs in AD and PD, the impact of SCs dysfunction on the alteration of brain energetics in these diseases remains poorly understood. The convergence of future progress in the study of SCs structure at high resolution and the refinement of animal models of AD and PD, as well as the use of iPSC-based and somatic cell-derived neurons, will be critical in understanding the biological relevance of the structural remodeling of SCs.
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Encéfalo/metabolismo , Metabolismo Energético/fisiologia , Mitocôndrias/metabolismo , Dinâmica Mitocondrial/fisiologia , Doenças Neurodegenerativas/metabolismo , Neurônios/metabolismo , Envelhecimento/metabolismo , Envelhecimento/patologia , Animais , Encéfalo/patologia , Complexo I de Transporte de Elétrons/genética , Complexo I de Transporte de Elétrons/metabolismo , Complexo IV da Cadeia de Transporte de Elétrons/genética , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Humanos , Mitocôndrias/patologia , Doenças Neurodegenerativas/patologia , Neurônios/patologia , Espécies Reativas de Oxigênio/metabolismoRESUMO
The use of fixed fibroblasts from familial and sporadic Alzheimer's disease patients has previously indicated an upregulation of mitochondria-ER contacts (MERCs) as a hallmark of Alzheimer's disease. Despite its potential significance, the relevance of these results is limited because they were not extended to live neurons. Here we performed a dynamic in vivo analysis of MERCs in hippocampal neurons from McGill-R-Thy1-APP transgenic rats, a model of Alzheimer's disease-like amyloid pathology. Live FRET imaging of neurons from transgenic rats revealed perturbed 'lipid-MERCs' (gap width <10â nm), while 'Ca2+-MERCs' (10-20â nm gap width) were unchanged. In situ TEM showed no significant differences in the lipid-MERCs:total MERCs or lipid-MERCs:mitochondria ratios; however, the average length of lipid-MERCs was significantly decreased in neurons from transgenic rats as compared to controls. In accordance with FRET results, untargeted lipidomics showed significant decreases in levels of 12 lipids and bioenergetic analysis revealed respiratory dysfunction of mitochondria from transgenic rats. Thus, our results reveal changes in MERC structures coupled with impaired mitochondrial functions in Alzheimer's disease-related neurons.This article has an associated First Person interview with the first author of the paper.
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Doença de Alzheimer , Retículo Endoplasmático , Mitocôndrias , Neurônios , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Modelos Animais de Doenças , Retículo Endoplasmático/genética , Retículo Endoplasmático/metabolismo , Retículo Endoplasmático/patologia , Humanos , Mitocôndrias/genética , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Neurônios/metabolismo , Neurônios/patologia , Ratos , Ratos TransgênicosRESUMO
The accumulation and spreading of protein tau in the human brain are major features of neurodegenerative disorders known as tauopathies. In addition to several subcellular abnormalities, tau aggregation within neurons seems capable of triggering endoplasmic reticulum (ER) stress and the consequent unfolded protein response (UPR). In metazoans, full activation of a complex ER-UPR network may restore proteostasis and ER function or, if stress cannot be solved, commit cells to apoptosis. Due to these alternative outcomes (survival or death), the pharmacological manipulation of ER-UPR has become the focus of potential therapies in many human diseases, including tauopathies. Here we update and analyze the experimental data from human brain, cellular, and animal models linking tau accumulation and ER-UPR. We further discuss mechanistic aspects and put the ER-UPR into perspective as a possible therapeutic target in this group of diseases.
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Encéfalo/metabolismo , Encéfalo/patologia , Estresse do Retículo Endoplasmático , Tauopatias/metabolismo , Tauopatias/patologia , Animais , Encéfalo/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Estresse do Retículo Endoplasmático/fisiologia , Humanos , Tauopatias/tratamento farmacológicoRESUMO
Alzheimer's disease (AD) is associated to depressed brain energy supply and impaired cortical and hippocampal synaptic function. It was previously reported in McGill-R-Thy1-APP transgenic (Tg(+/+)) rats that Aß deposition per se is sufficient to cause abnormalities in glucose metabolism and neuronal connectivity. These data support the utility of this animal model as a platform for the search of novel AD biomarkers based on bioenergetic status. Recently, it has been proposed that energy dysfunction can be dynamically tested in platelets (PLTs) of nonhuman primates. PLTs are good candidates to find peripheral biomarkers for AD because they may reflect in periphery the bioenergetics deficits and the inflammatory and oxidative stress processes taking place in AD brain. In the present study, we carried out a PLTs bioenergetics screening in advanced-age (12-14 months old) control (WT) and Tg(+/+) rats. Results indicated that thrombin-activated PLTs of Tg(+/+) rats showed a significantly lower respiratory rate, as compared to that measured in WT animals, when challenged with the same dose of FCCP (an uncoupler of oxidative phosphorylation). In summary, our results provide original evidence that PLTs bioenergetic profiling may reflect brain bioenergetics dysfunction mediated by Aß plaque accumulation. Further studies on human PLTs from control and AD patients are required to validate the usefulness of PLTs bioenergetics as a novel blood-based biomarker for AD.
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Doença de Alzheimer/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Plaquetas/metabolismo , Metabolismo Energético/fisiologia , Hipocampo/metabolismo , Placa Amiloide/metabolismo , Animais , Mitocôndrias/metabolismo , Ratos , Ratos TransgênicosRESUMO
The specific roles of Notch in progressive adulthood neurodegenerative disorders have begun to be unraveled in recent years. A number of independent studies have shown significant increases of Notch expression in brains from patients at later stages of sporadic Alzheimer's disease (AD). However, the impact of Notch canonical signaling activation in the pathophysiology of AD is still elusive. To further investigate this issue, 2-month-old wild-type (WT) and hemizygous McGill-R-Thy1-APP rats (Tg(+/-)) were injected in CA1 with lentiviral particles (LVP) expressing the transcriptionally active fragment of Notch, known as Notch Intracellular Domain (NICD), (LVP-NICD), or control lentivirus particles (LVP-C). The Tg(+/-) rat model captures presymptomatic aspects of the AD pathology, including intraneuronal amyloid beta (Aß) accumulation and early cognitive deficits. Seven months after LVP administration, Morris water maze test was performed, and brains isolated for biochemical and histological analysis. Our results showed a learning impairment and a worsening of spatial memory in LVP-NICD- as compared to LVP-C-injected Tg(+/-) rats. In addition, immuno histochemistry, ELISA multiplex, Western blot, RT-qPCR, and 1H-NMR spectrometry of cerebrospinal fluid (CSF) indicated that chronic expression of NICD promoted hippocampal vessel thickening with accumulation of Aß in brain microvasculature, alteration of blood-brain barrier (BBB) permeability, and a decrease of CSF glucose levels. These findings suggest that, in the presence of early Aß pathology, expression of NICD may contribute to the development of microvascular abnormalities, altering glucose transport at the BBB with impact on early decline of spatial learning and memory.
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Doença de Alzheimer/patologia , Vasos Sanguíneos/patologia , Glucose/metabolismo , Hipocampo/metabolismo , Transtornos da Memória/patologia , Receptores Notch/química , Receptores Notch/metabolismo , Memória Espacial , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/complicações , Doença de Alzheimer/fisiopatologia , Animais , Transporte Biológico , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/patologia , Região CA1 Hipocampal/metabolismo , Região CA1 Hipocampal/patologia , Modelos Animais de Doenças , Vetores Genéticos/metabolismo , Células HEK293 , Hipocampo/patologia , Hipocampo/fisiopatologia , Humanos , Inflamação/patologia , Lentivirus/genética , Transtornos da Memória/complicações , Transtornos da Memória/fisiopatologia , Microvasos/patologia , Domínios Proteicos , Espectroscopia de Prótons por Ressonância Magnética , Ratos Transgênicos , Ratos WistarRESUMO
The unfolded protein response (UPR) may be pathogenically related to Alzheimer's disease. Yet, the effects of chronic amyloid-ß42 (Aß42) accumulation and UPR activation upon neurotoxicity remain unclear. Here, we show that neuronal Aß42 expression in Drosophila activated the inositol-requiring protein-1/X-box binding protein 1 (XBP1) UPR branch before the onset of behavioral impairment and persisted with aging. Early upregulation of hsc3/BiP, a target of XBP1 and activating transcription factor 6 pathways, was also sustained in old animals. Downregulation of XBP1 enhanced neurotoxicity and the accumulation of Aß42 and polyubiquitinated proteins. Consistently, overexpression of spliced XBP1 reduced Aß42 and improved geotaxis in old flies. The activation of protein kinase RNA-like endoplasmic reticulum (ER) kinase contributed to the age-dependent geotaxis deficit. Spliced XBP1 gene targets ER degradation-enhancing mannosidase-like protein 1, ER degradation-enhancing mannosidase-like protein 2, and HRD1 were elevated in 5-day-old Aß42-expressing flies as compared to controls but not in 18-day-old flies. Our results indicate that inositol-requiring protein-1/XBP1 activation is neuroprotective and enhances Aß42 clearance. They also suggest that such response becomes inefficient with aging.
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Envelhecimento , Peptídeos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Drosophila melanogaster/genética , Drosophila melanogaster/fisiologia , Neuroproteção/genética , Fragmentos de Peptídeos/metabolismo , Transdução de Sinais , Proteína 1 de Ligação a X-Box/fisiologia , AnimaisRESUMO
The small ventral lateral neurons (sLNvs) constitute a central circadian pacemaker in the Drosophila brain. They organize daily locomotor activity, partly through the release of the neuropeptide pigment-dispersing factor (PDF), coordinating the action of the remaining clusters required for network synchronization. Despite extensive efforts, the basic principles underlying communication among circadian clusters remain obscure. We identified classical neurotransmitters released by sLNvs through disruption of specific transporters. Adult-specific RNAi-mediated downregulation of the glycine transporter or impairment of glycine synthesis in LNv neurons increased period length by nearly an hour without affecting rhythmicity of locomotor activity. Electrophysiological recordings showed that glycine reduces spiking frequency in circadian neurons. Interestingly, downregulation of glycine receptor subunits in specific sLNv targets impaired rhythmicity, revealing involvement of glycine in information processing within the network. These data identify glycinergic inhibition of specific targets as a cue that contributes to the synchronization of the circadian network.