Discovering novelty in sequential patterns: application for analysis of microarray data on Alzheimer disease

[Departement_IRSTEA]Territoires [TR1_IRSTEA]SYNERGIEInternational audienceAnalyzing microarrays data is still a great challenge since existing methods produce huge amounts of useless results. We propose a new method called NoDisco for discovering novelties in gene sequences obtained by applying data-mining techniques to microarray data. Method: We identify popular genes, which are often cited in the literature, and innovative genes, which are linked to the popular genes in the sequences but are not mentioned in the literature. We also identify popular and innovative sequences containing these genes. Biologists can thus select interesting sequences from the two sets and obtain the k-best documents. Results: We show the efficiency of this method by applying it on real data used to decipher the mechanisms underlying Alzheimer disease. Conclusion: The first selection of sequences based on popularity and innovation help experts focus on relevant sequences while the top-k documents help them understand the sequences

Lessons from the analysis of nonhuman primates for understanding human aging and neurodegenerative diseases

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)

Combining Gene Transfer and Nonhuman Primates to Better Understand and Treat Parkinson’s Disease

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

Exogenous LRRK2G2019S induces parkinsonian-like pathology in a nonhuman primate

Parkinson’s disease (PD) is the second most prevalent neurodegenerative disease among the elderly. To understand 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 impact 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 LRRK2 (leucine-rich repeat kinase 2) 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

Distinct Transcriptome Expression of the Temporal Cortex of the Primate Microcebus murinus during Brain Aging versus Alzheimer's Disease-Like Pathology

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

Expression of glutamate transporters in the medial and lateral vestibular nuclei during rat postnatal development.

The postnatal developmental expression and the distribution of the glutamate transporters (GLAST, GLT-1 and EAAC1) were analyzed in rat vestibular nuclei (VN), at birth and during the following 4 weeks. Analyses were performed using reverse transcriptase-polymerase chain reaction and immunoblotting of GLAST, GLT-1 and EAAC1 mRNA and protein during the postnatal development of the VN neurons and their afferent connections. We also studied the distribution of each glutamate transporter in the medial and lateral VN by use of immunocytochemistry and confocal microscopy. GLAST, GLT-1 and EAAC1 mRNA and protein were present in the VN at each developmental stage. GLAST was highly expressed mainly in glia from birth to the adult stage, its distribution pattern was heterogeneous depending on the region of the medial and lateral VN. GLT-1 expression increased dramatically during the second and third postnatal weeks. At least during the first postnatal week, GLT-1 was expressed in the soma of neurons. EAAC1 was detected in neurons and decreased from the third week. These temporal and regional patterns of GLAST, GLT-1 and EAAC1 suggest that they play different roles in the maturation of glutamatergic synaptic transmission in the medial and lateral VN during postnatal development

Old Gray Mouse Lemur Behavior, Cognition, and Neuropathology

International audienceNonhuman primate models are required to understand aging and age-related pathologies. The gray mouse lemur Microcebus murinus, a small prosimian primate, develops age-dependent deficits that are comparable to the decline observed during normal and pathological aging in humans. Importantly, not all old gray mouse lemurs are equally affected by age-related behavioral and cognitive problems. Some are profoundly impaired, while others perform as well as younger animals. Moreover, brain atrophy is detected only in some animals and thus appears to be an age-related pathological condition more than an inevitable effect of age. Finally, a subset of aged animals display neuropathological lesions observed also in Alzheimer's disease: β-amyloid deposition mainly in diffuse plaques and tau protein aggregation in some pyramidal neurons of the entorhinal cortex and hippocampus. Overall, these age-related changes indicate that gray mouse lemurs could be used as a potential translational model to study age-associated deficits and disorders

Aperçu de la diversité des modèles animaux dédiés à l’étude du vieillissement

Le haut degré de conservation des voies de signalisation impliquées dans la régulation de la longévité justifie l’utilisation d’organismes aussi variés que les nématodes, les souris, ou encore les lémuriens pour l’étude du vieillissement humain. La complémentarité de ces modèles permet d’aborder différentes questions : celles des interactions entre les facteurs génétiques et environnementau, de la conservation des fonctions auditives, de la lutte contre la sénescence des cellules souches neurales ou encore de l’exploration des aptitudes cérébrales depuis l’expression génique jusqu’aux comportements cognitifs et sociaux. Tout en différenciant les aspects physiologiques et pathologiques des processus liés à l’âge, nous soulignerons l’intérêt des technologies de pointe pour une meilleure compréhension des mécanismes régissant le vieillissement