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1.
Environ Health Perspect ; 128(1): 17011, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31939705

RESUMO

BACKGROUND: Pesticide residues have contaminated our environment and nutrition over the last century. Although these compounds are present at very low concentrations, their long-term effects on human health is of concern. The link between pesticide residues and Alzheimer's disease is not clear and difficult to establish. To date, no in vivo experiments have yet modeled the impact of this chronic contamination on neurodegenerative disorders. OBJECTIVES: We investigated the impact of fungicide residues on the pathological markers of Alzheimer's disease in a transgenic mouse model. METHODS: Transgenic (J20, hAPPSw/Ind) mice were chronically exposed to a cocktail of residues of cyprodinil, mepanipyrim, and pyrimethanil at 0.1µg/L in their drinking water for 9 months. We assessed the effects of fungicide residues on the pathological markers of the disease including Aß aggregates, neuroinflammation, and neuronal loss. Then, we studied the dynamics of Aß aggregation in vivo via a longitudinal study using two-photon microscopy. Finally, we investigated the molecular mechanisms involved in the production and clearance of Aß peptides. RESULTS: We found that a chronic exposure to three fungicide residues exacerbated aggregation, microgliosis, and neuronal loss. These fungicides also increased vascular amyloid aggregates reminiscent of cerebral amyloid angiopathy between 6 and 9 months of treatment. The mechanism of action revealed that fungicides promoted Aß peptide fibril formation in vitro and involved an in vivo overexpression of the levels of the ß-secretase-cleaving enzyme (BACE1) combined with impairment of Aß clearance through neprylisin (NEP). CONCLUSIONS: Chronic exposure of the J20 mouse model of Alzheimer's disease to a cocktail of fungicides, at the regulatory concentration allowed in tap water (0.1µg/L), strengthened the preexisting pathological markers: neuroinflammation, Aß aggregation, and APP ß-processing. We hypothesize prevention strategies toward pesticide long-term exposure may be an alternative to counterbalance the lack of treatment and to slow down the worldwide Alzheimer's epidemic. https://doi.org/10.1289/EHP5550.

2.
Front Mol Neurosci ; 12: 10, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30804750

RESUMO

Parkinson's disease (PD) is a progressive CNS disorder that is primarily associated with impaired movement. PD develops over decades and is linked to the gradual loss of dopamine delivery to the striatum, via the loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc). While the administration of L-dopa and deep brain stimulation are potent therapies, their costs, side effects and gradual loss of efficacy underlines the need to develop other approaches. Unfortunately, the lack of pertinent animal models that reproduce DA neuron loss and behavior deficits-in a timeline that mimics PD progression-has hindered the identification of alternative therapies. A complementary approach to transgenic animals is the use of nonhuman primates (NHPs) combined with the overexpression of disease-related genes using viral vectors. This approach may induce phenotypes that are not influenced by developmental compensation mechanisms, and that take into account the personality of animals. In this review article, we discuss the combination of gene transfer and NHPs to develop "genetic" models of PD that are suitable for testing therapeutic approaches.

3.
JCI Insight ; 3(14)2018 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-30046008

RESUMO

Parkinson's disease (PD) is the second most prevalent neurodegenerative disease among the elderly. To understand its pathogenesis and to test therapies, animal models that faithfully reproduce key pathological PD hallmarks are needed. As a prelude to developing a model of PD, we tested the tropism, efficacy, biodistribution, and transcriptional effect of canine adenovirus type 2 (CAV-2) vectors in the brain of Microcebus murinus, a nonhuman primate that naturally develops neurodegenerative lesions. We show that introducing helper-dependent (HD) CAV-2 vectors results in long-term, neuron-specific expression at the injection site and in afferent nuclei. Although HD CAV-2 vector injection induced a modest transcriptional response, no significant adaptive immune response was generated. We then generated and tested HD CAV-2 vectors expressing leucine-rich repeat kinase 2 (LRRK2) and LRRK2 carrying a G2019S mutation (LRRK2G2019S), which is linked to sporadic and familial autosomal dominant forms of PD. We show that HD-LRRK2G2019S expression induced parkinsonian-like motor symptoms and histological features in less than 4 months.


Assuntos
Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/metabolismo , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/farmacologia , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Adenovirus Caninos/genética , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Cheirogaleidae , Feminino , Perfilação da Expressão Gênica , Vetores Genéticos , Masculino , Mutação , Neurônios/efeitos dos fármacos , Técnicas Estereotáxicas , Distribuição Tecidual , Transcriptoma , Transdução Genética , Tropismo
4.
Neurotherapeutics ; 15(3): 751-769, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29181770

RESUMO

Spinal cord injuries (SCI) lead to major disabilities affecting > 2.5 million people worldwide. Major shortcomings in clinical translation result from multiple factors, including species differences, development of moderately predictive animal models, and differences in methodologies between preclinical and clinical studies. To overcome these obstacles, we first conducted a comparative neuroanatomical analysis of the spinal cord between mice, Microcebus murinus (a nonhuman primate), and humans. Next, we developed and characterized a new model of lateral spinal cord hemisection in M. murinus. Over a 3-month period after SCI, we carried out a detailed, longitudinal, behavioral follow-up associated with in vivo magnetic resonance imaging (1H-MRI) monitoring. Then, we compared lesion extension and tissue alteration using 3 methods: in vivo 1H-MRI, ex vivo 1H-MRI, and classical histology. The general organization and glial cell distribution/morphology in the spinal cord of M. murinus closely resembles that of humans. Animals assessed at different stages following lateral hemisection of the spinal cord presented specific motor deficits and spinal cord tissue alterations. We also found a close correlation between 1H-MRI signal and microglia reactivity and/or associated post-trauma phenomena. Spinal cord hemisection in M. murinus provides a reliable new nonhuman primate model that can be used to promote translational research on SCI and represents a novel and more affordable alternative to larger primates.


Assuntos
Modelos Animais de Doenças , Traumatismos da Medula Espinal/patologia , Traumatismos da Medula Espinal/fisiopatologia , Pesquisa Médica Translacional/métodos , Animais , Proteínas de Ligação ao Cálcio , Cheirogaleidae , Proteínas de Ligação a DNA/metabolismo , Comportamento Exploratório , Feminino , Seguimentos , Lateralidade Funcional , Proteína Glial Fibrilar Ácida/metabolismo , Humanos , Imagem por Ressonância Magnética , Masculino , Camundongos , Proteínas dos Microfilamentos , Microglia/patologia , Pessoa de Meia-Idade , Força Muscular/fisiologia , Junção Neuromuscular/patologia , Desempenho Psicomotor/fisiologia , Especificidade da Espécie , Medula Espinal/patologia , Fatores de Tempo , Trítio
5.
Vet Ophthalmol ; 21(3): 319-327, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-27624923

RESUMO

OBJECTIVE: The aim of this study was to assess the practicability of common tonometers used in veterinary medicine for rapid intraocular pressure (IOP) screening, to calibrate IOP values gained by the tonometers, and to define a reference IOP value for the healthy eye in a new primate model for aging research, the gray mouse lemur. STUDIED ANIMALS AND PROCEDURES: TonoVet® and the TonoPen™ measurements were calibrated manometrically in healthy enucleated eyes of mouse lemurs euthanized for veterinary reasons. For comparison of the practicability of both tonometers as a rapid IOP assessment tool for living mouse lemurs, the IOP of 24 eyes of 12 animals held in the hand was measured. To define a standard reference value for IOP in mouse lemurs, 258 healthy animals were measured using the TonoVet® . RESULTS: Intraocular pressure measurements for the TonoVet® can be corrected using the formula: y = 0.981 + (1.962*TonoVet® value), and those for the TonoPen™ using that of y = 5.38 + (1.426*TonoPen™ value). The calibrated IOP for a healthy mouse lemur eye was 20.3 ± 2.8 mmHg. The TonoVet® showed advantages in practicability, for example, small corneal contact area, short and painless corneal contact, shortened total time spent on investigation, as well as the more accurate measured values. IOP measurements of healthy mouse lemur eyes were not affected by age, sex, eye side, or colony. CONCLUSION: Tonometry using TonoVet® is the more practicable assessment tool for IOP measurement of the tiny eyes of living mouse lemurs. Pathological deviations can be identified based on the described reference value.


Assuntos
Cheirogaleidae , Pressão Intraocular , Tonometria Ocular/veterinária , Animais , Feminino , Masculino , Valores de Referência , Tonometria Ocular/instrumentação
6.
PeerJ ; 5: e3258, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28484672

RESUMO

BACKGROUND: Opacities of the lens are typical age-related phenomena which have a high influence on photoreception and consequently circadian rhythm. In mouse lemurs, a small bodied non-human primate, a high incidence (more than 50% when >seven years) of cataracts has been previously described during aging. Previous studies showed that photoperiodically induced accelerated annual rhythms alter some of mouse lemurs' life history traits. Whether a modification of photoperiod also affects the onset of age dependent lens opacities has not been investigated so far. The aim of this study was therefore to characterise the type of opacity and the mouse lemurs' age at its onset in two colonies with different photoperiodic regimen. METHODS: Two of the largest mouse lemur colonies in Europe were investigated: Colony 1 having a natural annual photoperiodic regime and Colony 2 with an induced accelerated annual cycle. A slit-lamp was used to determine opacities in the lens. Furthermore, a subset of all animals which showed no opacities in the lens nucleus in the first examination but developed first changes in the following examination were further examined to estimate the age at onset of opacities. In total, 387 animals were examined and 57 represented the subset for age at onset estimation. RESULTS: The first and most commonly observable opacity in the lens was nuclear sclerosis. Mouse lemurs from Colony 1 showed a delayed onset of nuclear sclerosis compared to mouse lemurs from Colony 2 (4.35 ± 1.50 years vs. 2.75 ± 0.99 years). For colony 1, the chronological age was equivalent to the number of seasonal cycles experienced by the mouse lemurs. For colony 2, in which seasonal cycles were accelerated by a factor of 1.5, mouse lemurs had experienced 4.13 ± 1.50 seasonal cycles in 2.75 ± 0.99 chronological years. DISCUSSION: Our study showed clear differences in age at the onset of nuclear sclerosis formation between lemurs kept under different photoperiodic regimes. Instead of measuring the chronological age, the number of seasonal cycles (N = four) experienced by a mouse lemur can be used to estimate the risk of beginning nuclear sclerosis formation. Ophthalmological examinations should be taken into account when animals older than 5-6 seasonal cycles are used for experiments in which unrestricted visual ability has to be ensured. This study is the first to assess and demonstrate the influence of annual photoperiod regime on the incidence of lens opacities in a non-human primate.

7.
Front Mol Neurosci ; 10: 90, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28420963

RESUMO

Neurons have inherent competence to regrow following injury, although not spontaneously. Spinal cord injury (SCI) induces a pronounced neuroinflammation driven by resident microglia and infiltrating peripheral macrophages. Microglia are the first reactive glial population after SCI and participate in recruitment of monocyte-derived macrophages to the lesion site. Both positive and negative influence of microglia and macrophages on axonal regeneration had been reported after SCI, raising the issue whether their response depends on time post-lesion or different lesion severity. We analyzed molecular alterations in microglia at several time-points after different SCI severities using RNA-sequencing. We demonstrate that activation of microglia is time-dependent post-injury but is independent of lesion severity. Early transcriptomic response of microglia after SCI involves proliferation and neuroprotection, which is then switched to neuroinflammation at later stages. Moreover, SCI induces an autologous microglial expression of astrocytic markers with over 6% of microglia expressing glial fibrillary acidic protein and vimentin from as early as 72 h post-lesion and up to 6 weeks after injury. We also identified the potential involvement of DNA damage and in particular tumor suppressor gene breast cancer susceptibility gene 1 (Brca1) in microglia after SCI. Finally, we established that BRCA1 protein is specifically expressed in non-human primate spinal microglia and is upregulated after SCI. Our data provide the first transcriptomic analysis of microglia at multiple stages after different SCI severities. Injury-induced microglia expression of astrocytic markers at RNA and protein levels demonstrates novel insights into microglia plasticity. Finally, increased microglia expression of BRCA1 in rodents and non-human primate model of SCI, suggests the involvement of oncogenic proteins after CNS lesion.

8.
Front Neurosci ; 9: 64, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25788873

RESUMO

Animal models are necessary tools for solving the most serious challenges facing medical research. In aging and neurodegenerative disease studies, rodents occupy a place of choice. However, the most challenging questions about longevity, the complexity and functioning of brain networks or social intelligence can almost only be investigated in nonhuman primates. Beside the fact that their brain structure is much closer to that of humans, they develop highly complex cognitive strategies and they are visually-oriented like humans. For these reasons, they deserve consideration, although their management and care are more complicated and the related costs much higher. Despite these caveats, considerable scientific advances have been possible using nonhuman primates. This review concisely summarizes their role in the study of aging and of the mechanisms involved in neurodegenerative disorders associated mainly with cognitive dysfunctions (Alzheimer's and prion diseases) or motor deficits (Parkinson's and related diseases).

9.
J Control Release ; 181: 22-31, 2014 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-24607662

RESUMO

Corneal transparency is maintained, in part, by specialized fibroblasts called keratocytes, which reside in the fibrous lamellae of the stroma. Corneal clouding, a condition that impairs visual acuity, is associated with numerous diseases, including mucopolysaccharidosis (MPS) type VII. MPS VII is due to deficiency in ß-glucuronidase (ß-glu) enzymatic activity, which leads to accumulation of glycosaminoglycans (GAGs), and secondary accumulation of gangliosides. Here, we tested the efficacy of canine adenovirus type 2 (CAV-2) vectors to transduce keratocyte in vivo in mice and nonhuman primates, and ex vivo in dog and human corneal explants. Following efficacy studies, we asked if we could treat corneal clouding by the injection a helper-dependent (HD) CAV-2 vector (HD-RIGIE) harboring the human cDNA coding for ß-glu (GUSB) in the canine MPS VII cornea. ß-Glu activity, GAG content, and lysosome morphology and physiopathology were analyzed. We found that HD-RIGIE injections efficiently transduced coxsackievirus adenovirus receptor-expressing keratocytes in the four species and, compared to mock-injected controls, improved the pathology in the canine MPS VII cornea. The key criterion to corrective therapy was the steady controlled release of ß-glu and its diffusion throughout the collagen-dense stroma. These data support the continued evaluation of HD CAV-2 vectors to treat diseases affecting corneal keratocytes.


Assuntos
Adenovirus Caninos/genética , Opacidade da Córnea/terapia , Substância Própria/enzimologia , Técnicas de Transferência de Genes , Glucuronidase/genética , Mucopolissacaridose VII/terapia , Adenovírus Humanos/genética , Animais , Cheirogaleidae , Opacidade da Córnea/enzimologia , Opacidade da Córnea/patologia , Substância Própria/patologia , Substância Própria/ultraestrutura , Modelos Animais de Doenças , Cães , Terapia Genética , Vetores Genéticos , Glicosaminoglicanos/metabolismo , Vírus Auxiliares , Humanos , Técnicas In Vitro , Lisossomos/enzimologia , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Confocal , Microscopia Eletrônica de Transmissão , Mucopolissacaridose VII/enzimologia , Mucopolissacaridose VII/patologia , Especificidade da Espécie
10.
Neurobiol Aging ; 34(11): 2613-22, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23796662

RESUMO

Anti-amyloid beta (Aß) immunotherapy provides potential benefits in Alzheimer's disease patients. Nevertheless, strategies based on Aß1-42 peptide induced encephalomyelitis and possible microhemorrhages. These outcomes were not expected from studies performed in rodents. It is critical to determine if other animal models better predict side effects of immunotherapies. Mouse lemur primates can develop amyloidosis with aging. Here we used old lemurs to study immunotherapy based on Aß1-42 or Aß-derivative (K6Aß1-30). We followed anti-Aß40 immunoglobulin G and M responses and Aß levels in plasma. In vivo magnetic resonance imaging and histology were used to evaluate amyloidosis, neuroinflammation, vasogenic edema, microhemorrhages, and brain iron deposits. The animals responded mainly to the Aß1-42 immunogen. This treatment induced immune response and increased Aß levels in plasma and also microhemorrhages and iron deposits in the choroid plexus. A complementary study of untreated lemurs showed iron accumulation in the choroid plexus with normal aging. Worsening of iron accumulation is thus a potential side effect of Aß-immunization at prodromal stages of Alzheimer's disease, and should be monitored in clinical trials.


Assuntos
Hemorragia Cerebral/induzido quimicamente , Hemorragia Cerebral/patologia , Plexo Corióideo/metabolismo , Imunização/efeitos adversos , Ferro/metabolismo , Adjuvantes Imunológicos/administração & dosagem , Fatores Etários , Peptídeos beta-Amiloides/sangue , Peptídeos beta-Amiloides/toxicidade , Animais , Hemorragia Cerebral/imunologia , Cheirogaleidae , Plexo Corióideo/efeitos dos fármacos , Modelos Animais de Doenças , Processamento de Imagem Assistida por Computador , Imunoglobulinas/sangue , Imagem por Ressonância Magnética , Fragmentos de Peptídeos/efeitos adversos , Fragmentos de Peptídeos/sangue , Fragmentos de Peptídeos/imunologia , Fragmentos de Peptídeos/toxicidade , Placa Amiloide/metabolismo , Placa Amiloide/patologia , Polissacarídeos Bacterianos/imunologia , Estatística como Assunto , Fatores de Tempo
11.
PLoS One ; 8(2): e56593, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23460806

RESUMO

Mouse lemurs are non-human primate models of cerebral aging and neurodegeneration. Much smaller than other primates, they recapitulate numerous features of human brain aging, including progressive cerebral atrophy and correlation between regional atrophy and cognitive impairments. Characterization of brain atrophy in mouse lemurs has been done by MRI measures of regional CSF volume and by MRI measures of regional atrophy. Here, we further characterize mouse lemur brain aging using ex vivo MR microscopy (31 µm in-plane resolution). First, we performed a non-biased, direct volumetric quantification of dentate gyrus and extended Ammon's horn. We show that both dentate gyrus and Ammon's horn undergo an age-related reorganization leading to a growth of the dentate gyrus and an atrophy of the Ammon's horn, even in the absence of global hippocampal atrophy. Second, on these first MR microscopic images of the mouse lemur brain, we depicted cortical and hippocampal hypointense spots. We demonstrated that their incidence increases with aging and that they correspond either to amyloid deposits or to cerebral microhemorrhages.


Assuntos
Envelhecimento/patologia , Cheirogaleidae/fisiologia , Hipocampo/patologia , Hipocampo/fisiopatologia , Hemorragias Intracranianas/fisiopatologia , Imagem por Ressonância Magnética , Placa Amiloide/fisiopatologia , Animais , Córtex Cerebral/patologia , Córtex Cerebral/fisiopatologia , Humanos , Hemorragias Intracranianas/complicações , Hemorragias Intracranianas/patologia , Placa Amiloide/complicações , Placa Amiloide/patologia
12.
Emerg Infect Dis ; 18(12): 2028-31, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23171544

RESUMO

We compared transmission characteristics for prions from L-type bovine spongiform encephalopathy and MM2-cortical sporadic Creutzfeldt-Jakob disease in the Syrian golden hamster and an ovine prion protein-transgenic mouse line and isolated distinct prion strains. Our findings suggest the absence of a causal relationship between these diseases, but further investigation is warranted.


Assuntos
Síndrome de Creutzfeldt-Jakob/transmissão , Encefalopatia Espongiforme Bovina/transmissão , Príons/patogenicidade , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Bovinos , Síndrome de Creutzfeldt-Jakob/mortalidade , Síndrome de Creutzfeldt-Jakob/patologia , Cricetinae , Encefalopatia Espongiforme Bovina/mortalidade , Encefalopatia Espongiforme Bovina/patologia , Humanos , Camundongos , Camundongos Transgênicos , Príons/metabolismo
13.
Emerg Infect Dis ; 18(1): 142-5, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22261009

RESUMO

We report transmission of atypical L-type bovine spongiform encephalopathy to mouse lemurs after oral or intracerebral inoculation with infected bovine brain tissue. After neurologic symptoms appeared, transmissibility of the disease by both inoculation routes was confirmed by detection of disease-associated prion protein in samples of brain tissue.


Assuntos
Cheirogaleidae , Encefalopatia Espongiforme Bovina/transmissão , Ração Animal , Animais , Encéfalo/patologia , Bovinos , Encefalopatia Espongiforme Bovina/classificação , Feminino , Masculino , Príons/metabolismo
14.
Neurobiol Aging ; 33(2): 431.e15-25, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21371784

RESUMO

We analyzed the cellular distribution of the pancreatic inflammatory protein lithostathine and its receptor EXTL3 in the brain of the lemurian primate Microcebus murinus which develops amyloid deposits along with aging. In adult animals (2-4.5 years old), lithostathine and EXTL3 immunoreactivities were largely distributed in the whole brain, and more intensively in almost all cortical layers and hippocampal formation. Lithostathine was observed in the perikarya and neurites of cortical neurons but also in glial cells in the border of the ventricle and the corpus callosum. In healthy aged animals (8-13 years old), highest densities of lithostathine-containing cells were observed, mainly in occipital and parietal cortex. In aged animals with Aß deposits, the increase in lithostathine immunoreactivity was lower as compared with aged animals. Noteworthy, lithostathine-immunopositive cells did almost never colocalize with Aß plaques. In conclusion, lithostathine immunoreactivity in adult Microcebus murinus appeared ubiquitous and particularly in visual, sensorial, and cognitive brain areas. Immunoreactivity increased with aging and appeared markedly affected in neuropathological conditions. Its possible neuroprotection or neurodegeneration role in Alzheimer pathology deserves therefore to be investigated.


Assuntos
Envelhecimento/metabolismo , Doença de Alzheimer/metabolismo , Encéfalo/metabolismo , Cheirogaleidae/metabolismo , Litostatina/metabolismo , Envelhecimento/patologia , Doença de Alzheimer/patologia , Animais , Encéfalo/patologia , Distribuição Tecidual
15.
Neurobiol Aging ; 32(5): 894-906, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-19564059

RESUMO

We assessed the regional brain atrophy in mouse lemur primates from 4.7T T2-weighted magnetic resonance images. Thirty animals aged from 1.9 to 11.3 years were imaged. Sixty-one percent of the 23 animals older than 3 years involved in the study displayed an atrophy process. Cross-sectional analysis suggests that the atrophy follows a gradual pathway, starting in the frontal region then involving the temporal and/or the parietal part of the brain and finally the occipital region. Histological evaluation of five animals selected according to various stages of atrophy suggested that extracellular amyloid deposits and tau pathology cannot explain by themselves this atrophy and that intracellular amyloid deposition is more closely linked to this pathology. This study suggests that most of the age-related atrophy occurring in mouse lemurs is caused by one clinical, evolving, pathological process. The ability to follow this pathology non-invasively by MRI will allow to further characterize it and evaluate its relationship with neuropathological lesions that are involved in human diseases such as Alzheimer.


Assuntos
Envelhecimento/patologia , Encéfalo/patologia , Animais , Atrofia/patologia , Cheirogaleidae , Imagem por Ressonância Magnética , Placa Amiloide/patologia , Proteínas tau/fisiologia
16.
PLoS One ; 5(9)2010 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-20862281

RESUMO

Aging is the primary risk factor of neurodegenerative disorders such as Alzheimer's disease (AD). However, the molecular events occurring during brain aging are extremely complex and still largely unknown. For a better understanding of these age-associated modifications, animal models as close as possible to humans are needed. We thus analyzed the transcriptome of the temporal cortex of the primate Microcebus murinus using human oligonucleotide microarrays (Affymetrix). Gene expression profiles were assessed in the temporal cortex of 6 young adults, 10 healthy old animals and 2 old, "AD-like" animals that presented ß-amyloid plaques and cortical atrophy, which are pathognomonic signs of AD in humans. Gene expression data of the 14,911 genes that were detected in at least 3 samples were analyzed. By SAM (significance analysis of microarrays), we identified 47 genes that discriminated young from healthy old and "AD-like" animals. These findings were confirmed by principal component analysis (PCA). ANOVA of the expression data from the three groups identified 695 genes (including the 47 genes previously identified by SAM and PCA) with significant changes of expression in old and "AD-like" in comparison to young animals. About one third of these genes showed similar changes of expression in healthy aging and in "AD-like" animals, whereas more than two thirds showed opposite changes in these two groups in comparison to young animals. Hierarchical clustering analysis of the 695 markers indicated that each group had distinct expression profiles which characterized each group, especially the "AD-like" group. Functional categorization showed that most of the genes that were up-regulated in healthy old animals and down-regulated in "AD-like" animals belonged to metabolic pathways, particularly protein synthesis. These data suggest the existence of compensatory mechanisms during physiological brain aging that disappear in "AD-like" animals. These results open the way to new exploration of physiological and "AD-like" aging in primates.


Assuntos
Envelhecimento/genética , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Encéfalo/crescimento & desenvolvimento , Cheirogaleidae/genética , Perfilação da Expressão Gênica , Lobo Temporal/metabolismo , Fatores Etários , Envelhecimento/metabolismo , Envelhecimento/patologia , Doença de Alzheimer/metabolismo , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Cheirogaleidae/crescimento & desenvolvimento , Cheirogaleidae/metabolismo , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica , Humanos , Masculino , Análise de Sequência com Séries de Oligonucleotídeos , Lobo Temporal/crescimento & desenvolvimento , Lobo Temporal/patologia
17.
Neurobiol Dis ; 39(2): 211-20, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20399858

RESUMO

No effective treatment currently exists for prion diseases and therefore the development of experimental non-human primate models of prion neurotoxicity, to better understand the underlying mechanism and to test new treatments relevant to humans, represents an urgent medical need. However, the establishment of such models is challenging due to animal welfare and cost considerations. We describe here the use of Microcebus murinus retina, in primary cultures and in vivo, as a new experimental primate model to rapidly examine the effects in the central nervous system of PrP(106-126), a neurotoxic fragment of the human prion protein. We demonstrate that PrP(106-126) triggered rod photoreceptor cell loss by apoptosis and a change in morphology of microglial cells in mixed neuronal-glial cultures of retinal cells. In addition, 2days after intravitreal injection of PrP(106-126), retinas showed a significant increase in the number of apoptotic nuclei, mainly in the ganglion cell layer.


Assuntos
Modelos Animais de Doenças , Síndromes Neurotóxicas/patologia , Príons/metabolismo , Retina/metabolismo , Retina/patologia , Análise de Variância , Animais , Morte Celular/efeitos dos fármacos , Células Cultivadas , Cheirogaleidae , Proteína Glial Fibrilar Ácida/metabolismo , Marcação In Situ das Extremidades Cortadas/métodos , Microscopia Eletrônica de Transmissão/métodos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/ultraestrutura , Síndromes Neurotóxicas/etiologia , Parvalbuminas/metabolismo , Fragmentos de Peptídeos/toxicidade , Príons/toxicidade , Retina/ultraestrutura , Rodopsina/metabolismo , Vimentina/metabolismo
18.
Neurobiol Learn Mem ; 94(1): 100-6, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20403446

RESUMO

Microcebus murinus, a mouse lemur primate appears to be a valuable model for cerebral aging study and for Alzheimer's disease model since they can develop beta-amyloid plaques with age. Although the biological and biochemical analyses of cerebral aging are well documented, the cognitive abilities of this primate have not been thoroughly characterized. In this study, we adapted a spatial working memory procedure described in rodents, the sequential choice task in the three-panel runway, to mouse lemurs. We analyzed the age-related differences in a procedural memory task in the absence or presence of visual cues. Sixty percent of young adult and 48% of aged lemurs completed the exploratory, choice habituation and testing phases at the beginning of the procedure. Young adult lemurs showed a higher level of perseverative errors compared with aged animals, particularly in the presence of visual stimuli. Over trials, old animals made more reference errors compared to young ones that improved quickly their performances under random level. No significant improvement was observed in young adults and old ones over sessions. This study showed that behavioural performances of M. murinus assessed on the sequential choice task in the three-panel runway markedly differ from the previously reported abilities of rodents. The behavioural response of young adult lemurs was influenced by novelty-related anxiety that contributed to their performance in terms of perseverative errors. Conversely, aged lemurs showed less perseverative errors, a rapid habituation to the three-panel runway maze, but made more memory errors. Overall, these findings demonstrate the feasibility to use the three-panel runway task in assessing memory performance, particularly in aged mouse lemurs.


Assuntos
Envelhecimento/psicologia , Cheirogaleidae/psicologia , Aprendizagem em Labirinto , Memória , Animais , Ansiedade , Estudos de Coortes , Sinais (Psicologia) , Comportamento Exploratório , Habituação Psicofisiológica , Memória de Curto Prazo , Testes Neuropsicológicos , Percepção Espacial , Fatores de Tempo , Percepção Visual
19.
Vaccine ; 27(7): 957-64, 2009 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-19114076

RESUMO

We have been developing Abeta derivative vaccines with the objective to improve the safety of Abeta targeting immunotherapy. Our Abeta homologs are designed to have less direct toxicity and to produce a modified immune response compared to Abeta. In extensive mouse studies, all our vaccines have improved cognition in transgenic mice while eliciting different immune responses and reducing brain amyloid burden to a variable degree. While we are continuing to characterize these vaccines in mice, in preparation for studies in old primates and for human trials we assessed their effect in young lemur primates (n=25) that with age develop Abeta plaques and tau aggregates as seen in Alzheimer's disease. In the primates, all the peptides administered with alum adjuvant elicited a moderate to robust anti-Abeta IgM response. Abeta1-42, K6Abeta1-30 and K6Abeta1-30[E(18)E(19)] resulted in a high anti-Abeta IgG response, whereas Abeta1-30[E(18)E(19)] produced a weaker more variable IgG titer. Notably, 22 weeks after the 3rd immunization, IgM and IgG levels in derivative-vaccinated primates were similar to preimmune values whereas Abeta1-42 treated primates maintained a moderate IgG titer. The increase in antibodies that recognized Abeta1-40 often correlated with increase in Abeta1-40 in plasma, which suggests that the antibodies were binding to Abeta in vivo. Interestingly, significant transient weight gain was observed (K6Abeta1-30-, Abeta1-30[E(18)E(19)]- and Abeta1-42-treated) or a trend in the same direction (K6Abeta1-30[E(18)E(19)]-treated, adjuvant controls) following the injections. Based on these findings, we have chosen K6Abeta1-30 for immunizations in old primates as the antibody response to this vaccine was less variable compared to other Abeta derivatives. Our present findings indicate that most of our Abeta derivatives elicit a substantial antibody response in primates, and importantly this effect is reversible which enhances the safety profile of our approach.


Assuntos
Vacinas contra Alzheimer/imunologia , Peptídeos beta-Amiloides/sangue , Peptídeos beta-Amiloides/imunologia , Formação de Anticorpos , Fragmentos de Peptídeos/sangue , Fragmentos de Peptídeos/imunologia , Plasma/química , Adjuvantes Imunológicos/administração & dosagem , Compostos de Alúmen/administração & dosagem , Animais , Peso Corporal , Encéfalo/patologia , Cheirogaleidae , Feminino , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Masculino
20.
PLoS One ; 3(7): e2773, 2008 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-18648643

RESUMO

Classical drug therapies against prion diseases have encountered serious difficulties. It has become urgent to develop radically different therapeutic strategies. Previously, we showed that VSV-G pseudotyped FIV derived vectors carrying dominant negative mutants of the PrP gene are efficient to inhibit prion replication in chronically prion-infected cells. Besides, they can transduce neurons and cells of the lymphoreticular system, highlighting their potential use in gene therapy approaches. Here, we used lentiviral gene transfer to deliver PrPQ167R virions possessing anti-prion properties to analyse their efficiency in vivo. Since treatment for prion diseases is initiated belatedly in human patients, we focused on the development of a curative therapeutic protocol targeting the late stage of the disease, either at 35 or 105 days post-infection (d.p.i.) with prions. We observed a prolongation in the lifespan of the treated mice that prompted us to develop a system of cannula implantation into the brain of prion-infected mice. Chronic injections of PrPQ167R virions were done at 80 and 95 d.p.i. After only two injections, survival of the treated mice was extended by 30 days (20%), accompanied by substantial improvement in behaviour. This delay was correlated with: (i) a strong reduction of spongiosis in the ipsilateral side of the brain by comparison with the contralateral side; and (ii) a remarkable decrease in astrocytic gliosis in the whole brain. These results suggest that chronic injections of dominant negative lentiviral vectors into the brain, may be a promising approach for a curative treatment of prion diseases.


Assuntos
Terapia Genética/métodos , Doenças Priônicas/genética , Doenças Priônicas/terapia , Animais , Astrócitos/citologia , Encéfalo/patologia , Modelos Animais de Doenças , Humanos , Lentivirus/genética , Glicoproteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Polimorfismo Genético , Proteínas PrPC/metabolismo , Príons/metabolismo , Fatores de Tempo , Proteínas do Envelope Viral/metabolismo
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