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

Publication date: August 2018
Source:Neurobiology of Aging, Volume 68
Author(s): Robert Adalbert, Stefan Milde, Claire Durrant, Kunie Ando, Virginie Stygelbout, Zehra Yilmaz, Stacey Gould, Jean-Pierre Brion, Michael P. Coleman
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 MAPT^P301L knockin mice, a genetic model of frontotemporal dementia with parkinsonism-17T. In this study, we further characterized the axonal transport of mitochondria in younger MAPT^P301L 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 MAPT^P301L/P301L knockin animals. Surprisingly, we found that in the presence of the amyloid precursor protein mutations, MAPT^P301L/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.



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