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Interaction between a MAPT variant causing frontotemporal dementia and mutant APP affects axonal transport.

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Adalbert, Robert 
Milde, Stefan 
Durrant, Claire 
Ando, Kunie 
Stygelbout, Virginie 


In Alzheimer's disease, many indicators point to a central role for poor axonal transport, but the potential for stimulating axonal transport to alleviate the disease remains largely untested. Previously, we reported enhanced anterograde axonal transport of mitochondria in 8- to 11-month-old MAPTP301L knockin mice, a genetic model of frontotemporal dementia with parkinsonism-17T. In this study, we further characterized the axonal transport of mitochondria in younger MAPTP301L mice crossed with the familial Alzheimer's disease model, TgCRND8, aiming to test whether boosting axonal transport in young TgCRND8 mice can alleviate axonal swelling. We successfully replicated the enhancement of anterograde axonal transport in young MAPTP301L/P301L knockin animals. Surprisingly, we found that in the presence of the amyloid precursor protein mutations, MAPTP301L/P3101L impaired anterograde axonal transport. The numbers of plaque-associated axonal swellings or amyloid plaques in TgCRND8 brains were unaltered. These findings suggest that amyloid-β promotes an action of mutant tau that impairs axonal transport. As amyloid-β levels increase with age even without amyloid precursor protein mutation, we suggest that this rise could contribute to age-related decline in frontotemporal dementia.



Alzheimer's disease, Axonal transport, , FTDP-17T, Mitochondria, P301L mutation, Aging, Alzheimer Disease, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Animals, Axonal Transport, Brain, Disease Models, Animal, Frontotemporal Dementia, Genetic Association Studies, Genetic Variation, Male, Mice, Inbred C57BL, Mice, Transgenic, Mitochondria, Mutation, Plaque, Amyloid, tau Proteins

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Neurobiol Aging

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Elsevier BV
Alzheimer's Research UK (ARUK-PG2015-24)
Medical Research Council (MR/L003813/1)
This work was supported by Alzheimer’s Research UK (ART/PG2009/2 to R.A.), MRC project grant (MR/L003813/1 to R.A., S.G.), Medical Research Council studentship (S.M.), Alzheimer’s Research UK studentship (ARUKPhD2013-13 to C.D.), Biotechnology and Biological Sciences Research Council Institute Strategic Programme Grant (M.P.C.), the Foundation for Alzheimer Research (FRA/SAO) (JPB) and the Belgian F.N.R.S. (K.A and JPB).