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• W2003123229 abstract "Recent Genome-Wide Association Studies have identified two genes (PICALM and BIN1) involved in physiological vesicular trafficking as potentially harbouring genetic variants associated with risk for late onset sporadic Alzheimer's disease. Several other genes involved in vesicular trafficking (SORL1 SORCS1, SORCS2) have been associated with risk for AD, and have apparently caused this risk by altering APP processing, and increasing the production of Abeta. We therefore hypothesised that that these other genes might also alter APP trafficking, particularly trafficking related to synaptic activity and synaptic vesicle recycling in neurons. PICALM and BIN1 cDNAs, and PICALM and BIN1 shRNAs were cloned into Lentiviral expression vectors that provided either constitutive expression or inducible expression under tetracycline control. Stable cell lines were then generated using a variety of cell types (e.g. HEK293, HeLa, SHSY5Y). We then measured Abeta and APPs_alpha, APPs_beta levels in the conditioned media and in cell lysates, and we investigated the levels of mature and immature APP in the cell lysates. In cell lines expressing PICALM shRNA molecules, there was a small (20%), but consistent reduction in Abeta secretion. The effects of PICALM overexpression are currently being investigated. In cell lines expressing wild-type APP and BIN1 shRNAs, there was no consistent alteration in Abeta secretion or on APP processing. Similarly, in cell lines over-expressing wild-type APP and BIN1 cDNAs, there was also no consistent alteration in Abeta secretion or on APP processing. However, in cell lines co-expressing APP_swedish, although there were no changes in Abeta secretion, there were subtle changes in APPs_alpha levels after either BIN1 suppression or BIN1 overexpression, suggesting that while BIN1 had no effect on APP entering into the late endosome–lysosome pathway for BACE and gamma-secretase cleavage, it did affect APP_Swedish processing on the cell surface. In strong contrast to the effects of the overexpression/knockdown of SORL1, SORCS1, SORC2, and other genes involved in the retromer pathway, modulation of PICALM and BIN1 expression have only modest effects on APP processing. These results, which will need to be confirmed by further studies, suggest several possible conclusions. First, while the SNPs associated with AD on GWAS fall within/close to the BIN1 and PICALM genes, it has not yet been proven that BIN1 and PICALM are in fact the functional elements impacted by these disease-associated SNPs. It is currently still formally possible that the SNPs in BIN1 and PICALM genes might actually influence the expression of other genes nearby. Second, it is possible that the disease-causing SNPs do alter BIN1 and PICALM function, but do so by causing a gain-of-toxic function which is not predictable via simple up- or down-regulation of BIN1 and PICALM expression. Finally, it is possible that the disease-causing SNPs do effect BIN1 and PICALM function, but this function does not modulate APP processing and Abeta production, but might affect some other downstream aspect of Abeta toxicity." @default.
• W2003123229 created "2016-06-24" @default.
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• W2003123229 date "2011-07-01" @default.
• W2003123229 modified "2023-09-27" @default.
• W2003123229 title "F2-01-05: Genes Found by GWAS in Alzheimer's Disease: Comparing VPS10-Containing Receptors with BIN1 and CALM1" @default.
• W2003123229 doi "https://doi.org/10.1016/j.jalz.2011.05.819" @default.
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