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Theses

Endosomes élargis et cholestérol : De la trisomie 21 à la maladie d'Alzheimer

Abstract : Enlarged endosomes are believed to be the first morphological change observed in Alzheimer's disease brains (AD). They are found in sporadic cases with no pathological evidence of AD yet, in Down syndrome (DS) as early as 28 weeks of gestation. DS patients developped AD because amyloïd peptides found in seniles plaques, were generated from APP (amyloid precursor protein), a gene localized on the chromosome 21. As APP and amyloid peptide seems not to be involved in enlarged endosomes, we thus searched for other factors that could modify the endosome morphology in AD and DS. We found unexpectedly that increased membrane cholesterol was associated with the appearance of enlarged endosomes together with increased APP endocytosis and Aß secretion in cultured neuronal and non neuronal cells. This effect of cholesterol was inhibited by siRNA against clathrin and by mutants of proteins involved in the formation of early endosomes (dynamin2 and Rab5). We suggest that the endo-lysosomal pathway of APP is regulated by cholesterol, in a Rab5 and clathrin dependent manner. As levels of total cholesterol are increased in the brains of AD patients we postulate that this raise could be responsible for the enhanced internalization of APP in enlarged endosomes and the overproduction of Aß. In search for new genes involved in the enlargment of early endosomes, we used lymphoblastoid cell lines (LCL) and blood mononuclear cells (BMC) from DS patients carrying full or partial trisomy 21. Using confocal microscopy, we showed that the mean size of the endosomes was significantly increased (+35%) in LCLs and BMC. Enlarged endosomes were absent in the 3 LCLs carrying APP microduplications. This result suggested that APP is not involved in the enlargement of early endosomes in this cell type. In four out of seven LCLs from DS patients carrying partial trisomy 21 we could very easily identify enlarged endosomes. By correlating the presence of enlarged endosomes to the triplicated genomic segment from Hsa21 we identified SYNJ1 as a candidate gene. SYNJ1 gene codes for the phosphoinositide phosphatase synaptojanin 1 protein, a key regulator of the signalling phospholipids phosphatidylinositol-4,5-biphosphate (PtdIns(4,5)P2). We observed abnormally large endosomes in SH-SY5Y cells transfected with SYNJ1 plasmid. We conclude that deregulation of PtdIns(4,5)P2 homeostasy by synapyojanin 1 over-expression can lead to the enlargement of early endosomes.
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https://pastel.archives-ouvertes.fr/pastel-00579137
Contributor : Ecole Espci Paristech <>
Submitted on : Wednesday, March 23, 2011 - 10:35:22 AM
Last modification on : Wednesday, October 14, 2020 - 3:43:07 AM
Long-term archiving on: : Friday, June 24, 2011 - 2:44:42 AM

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  • HAL Id : pastel-00579137, version 1

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Jack-Christophe Cossec. Endosomes élargis et cholestérol : De la trisomie 21 à la maladie d'Alzheimer. Neurosciences [q-bio.NC]. Université Paris-Diderot - Paris VII, 2009. Français. ⟨pastel-00579137⟩

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