biostudies-literatureStokin GBNEI NIH HHSHoward Hughes Medical InstitutePHS HHSNIGMS NIH HHS3474-86https://www.ebi.ac.uk/biostudies/studies/S-EPMC2722897biostudies-literatureUnknown17(22)Overexpression of amyloid precursor protein (APP), as well as mutations in the APP and presenilin genes, causes rare forms of Alzheimer's disease (AD). These genetic changes have been proposed to cause AD by elevating levels of amyloid-beta peptides (Abeta), which are thought to be neurotoxic. Since overexpression of APP also causes defects in axonal transport, we tested whether defects in axonal transport were the result of Abeta poisoning of the axonal transport machinery. Because directly varying APP levels also alters APP domains in addition to Abeta, we perturbed Abeta generation selectively by combining APP transgenes in Drosophila and mice with presenilin-1 (PS1) transgenes harboring mutations that cause familial AD (FAD). We found that combining FAD mutant PS1 with FAD mutant APP iHuman molecular geneticsAmyloid precursor protein-induced axonopathies are independent of amyloid-beta peptides.PMC2722897GM35252R01 EY007042-22AGO22595R01 EY007042Williams DSGunawardena SRoberts EAMcGowan EAlmenar-Queralt AStokin GBMount SLFalzone TKim JRodrigues EMGoldstein LSLillo CfalseAmyloid precursor protein-induced axonopathies are independent of amyloid-beta peptides.Overexpression of amyloid precursor protein (APP), as well as mutations in the APP and presenilin genes, causes rare forms of Alzheimer's disease (AD). These genetic changes have been proposed to cause AD by elevating levels of amyloid-beta peptides (Abeta), which are thought to be neurotoxic. Since overexpression of APP also causes defects in axonal transport, we tested whether defects in axonal transport were the result of Abeta poisoning of the axonal transport machinery. Because directly varying APP levels also alters APP domains in addition to Abeta, we perturbed Abeta generation selectively by combining APP transgenes in Drosophila and mice with presenilin-1 (PS1) transgenes harboring mutations that cause familial AD (FAD). We found that combining FAD mutant PS1 with FAD mutant APP i2008-01-01T00:00:00Z2008 Nov2025-04-19T05:37:17.236Z2019-03-27T00:24:06ZS-EPMC27228971869489810.1093/hmg/ddn240