La maladie d’Alzheimer à forme tardive, exempte de mutations, représente près de 99% des 850 000 cas répertoriés en France. Hormis l’âge, des facteurs génétiques comme BIN1 apparaissent déterminant dans l’établissement de l’amyloïdopathie et de la tauopathie, marqueurs constitutifs de cette maladie. Le travail de thèse est basé sur l’étude d’une surexpression du gène humain de BIN1 et de son impact dans un contexte murin de tauopathie. La surexpression seule de BIN1 entraine des défauts mnésiques à court terme associés à des anomalies cellulaires et moléculaires au niveau de la voie temporo-hippocampique. Ces altérations sont exacerbées par la combinaison de la souris TgBIN1 avec le modèle de tauopathie, à la fois chez les mâles et les femelles. Pour autant il apparait que la surexpression de BIN1 préserve la mémoire spatiale dépendamment de l’âge et du sexe. L’hippocampe apparait en grande partie préservé des inclusions intracellulaires de Tau et la myéline des fibres axonales est retrouvé intacte. Ces éléments mettent en évidence que BIN1 est un acteur important dans l’établissement de la tauopathie et que son activité neuro-protectrice peut être médiée par un complexe moléculaire direct impliquant à la fois Tau et RNT4-A/Nogo-A. / Late Onset Alzheimer Disease represents more than 99% of total Alzheimer cases and it is not caused by genetic mutations. Among risk factors such as age, genetic compounds as BIN1 appear to be determinant for the pathological process establishment. This study aims to determine the BIN1 overexpression effect in mice and in a tauopathy context. In this study, BIN1 overexpression alone caused short term memory impairments linked with the cellular and molecular abnormalities. These disorders are exacerbated by a combination of TgBIN1 mice with a tauopathy model, both in males and females. Surprisingly, BIN1 overexpression rescued long term and spatial memory regarding the age and sex. Hippocampus appeared to be preserved from intracellular Tau inclusions. Moreover, fornix myelin is found intact. These elements highlighted BIN1 which is a key gene in tauopathie establishment. BIN1 neuroprotective activity is mediated by direct molecular interactions both with Tau and RTN4-A/Nogo-A.

Schizophrenia may result from altered gene expression leading to abnormal neurodevelopment. In a search for genes with altered expression in schizophrenia, cDNA library subtractive hybridization experiments using post-mortem human frontal cerebral cortices from schizophrenia individuals and neurological controls were performed. I found the mRNA of two neurodevelopmentally important genes, Nogo (RTN4) and calcium/calmodulin-dependent protein kinase II beta (CaMKIIβ), to be overexpressed in post-mortem frontal cortex tissues from patients who suffered with schizophrenia. I used the quantitative real-time polymerase chain reaction method to determined the mRNA levels of these genes in tissues from age- and sex-matched individuals. Nogo is a myelin-associated protein which inhibits the outgrowth of neurites and nerve terminals. The gene produces three splice variants, Nogo-A, B and C. I found Nogo-C mRNA to be overexpressed by 26% in schizophrenia. I also found a 17% reduction of Nogo-B mRNA in samples from individuals who had been diagnosed with severe depression. Furthermore, I showed that there is a direct correlation between the expression of both Nogo-A and -C and the presence of a CAA insert in the 3’UTR of the Nogo gene. CaMKII is a kinase localized at the postsynaptic density. The holoenzyme is primarily composed of the subunits α and β, encoded by two separate genes. It influences the expression of many neuroreceptors, in particular receptors of the glutamatergic pathway. CaMKII also mediates neural maturation during puberty, a time of onset of schizophrenia. The expression of CaMKIIα was elevated 29% in frontal cortex tissues of patients who suffered from depression. The expression of CaMKIIβ was elevated 27% in tissues of schizophrenia patients and 36% in tissues of patients diagnosed with depression. Upregulation of CaMKIIβ was associated with the presence of the CAA insert in at least one copy of the Nogo gene in a group containing both healthy subjects and patients with mental illness, possibly linking the CaMKII and Nogo pathways. The values for the expression of Nogo, CaMKIIα and CaMKIIβ were normalized to β-glucuronidase expression to minimize the effects of mRNA degradation. These results confirm that upregulation of Nogo-C and CaMKIIβ is likely associated with schizophrenia.

Schizophrenia may result from altered gene expression leading to abnormal neurodevelopment. In a search for genes with altered expression in schizophrenia, cDNA library subtractive hybridization experiments using post-mortem human frontal cerebral cortices from schizophrenia individuals and neurological controls were performed. I found the mRNA of two neurodevelopmentally important genes, Nogo (RTN4) and calcium/calmodulin-dependent protein kinase II beta (CaMKIIβ), to be overexpressed in post-mortem frontal cortex tissues from patients who suffered with schizophrenia. I used the quantitative real-time polymerase chain reaction method to determined the mRNA levels of these genes in tissues from age- and sex-matched individuals. Nogo is a myelin-associated protein which inhibits the outgrowth of neurites and nerve terminals. The gene produces three splice variants, Nogo-A, B and C. I found Nogo-C mRNA to be overexpressed by 26% in schizophrenia. I also found a 17% reduction of Nogo-B mRNA in samples from individuals who had been diagnosed with severe depression. Furthermore, I showed that there is a direct correlation between the expression of both Nogo-A and -C and the presence of a CAA insert in the 3’UTR of the Nogo gene. CaMKII is a kinase localized at the postsynaptic density. The holoenzyme is primarily composed of the subunits α and β, encoded by two separate genes. It influences the expression of many neuroreceptors, in particular receptors of the glutamatergic pathway. CaMKII also mediates neural maturation during puberty, a time of onset of schizophrenia. The expression of CaMKIIα was elevated 29% in frontal cortex tissues of patients who suffered from depression. The expression of CaMKIIβ was elevated 27% in tissues of schizophrenia patients and 36% in tissues of patients diagnosed with depression. Upregulation of CaMKIIβ was associated with the presence of the CAA insert in at least one copy of the Nogo gene in a group containing both healthy subjects and patients with mental illness, possibly linking the CaMKII and Nogo pathways. The values for the expression of Nogo, CaMKIIα and CaMKIIβ were normalized to β-glucuronidase expression to minimize the effects of mRNA degradation. These results confirm that upregulation of Nogo-C and CaMKIIβ is likely associated with schizophrenia.