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P2‐248: Arf4 regulates dendritic spine development in mouse primary neurons
Author(s) -
Jain Sachi,
Brodbeck Jens,
Bernardo Aubrey,
Walker David,
Huang Yadong
Publication year - 2010
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2010.05.1297
Subject(s) - dendritic spine , wild type , gtpase , hippocampus , biology , hippocampal formation , genetically modified mouse , microbiology and biotechnology , mutant , transgene , endocrinology , gene , biochemistry
co-immunoprecipitated with DISC1 at the endogenous protein level. Knockdown of DISC1 (lentivirus-mediated shRNA to DISC1) in mature primary cortical neurons, elicited no change in the levels of full-length APP (both mature and immature isoforms). In contrast, knockdown of DISC1 led to a significant increase in the levels of intracellular APP-C-terminal fragments C83 and C99. Knockdown of DISC1 also significantly enhanced sAPPa levels. Interestingly, we observed that DISC1 knockdown significantly decreased the levels of Ab42 and Ab40. The knockdown effects of DISC1 by RNAi on APP-CTFs, sAPPa and Ab 42/40 were successfully rescued by co-expression of wild-type DISC1. In the next step, we addressed whether DISC1 influences APP processing by using DISC1 knockout (KO) mice. We observed a significant increase in both C83 and C99 APP CTFs, with no change in the total APP levels in the DISC1 KO mice, as was the case in the primary neurons. Conclusions: DISC1 affects the processing of APP and generation of Ab in primary neuron cultures. Our goal is to characterize a novel mechanism of the regulation of APP processing/metabolism by DISC1.