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

Robert Adalbert,Stefan Milde,Jean-Pierre Brion,Michael P Coleman,Stacey Gould,Zehra Yilmaz,Kunie Ando,Virginie Stygelbout,Claire Durrant

doi:10.1016/j.neurobiolaging.2018.03.033

Robert Adalbert, Stefan Milde + Show 7 more

Open Access

https://doi.org/10.1016/j.neurobiolaging.2018.03.033

Copy DOI

Abstract

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.

Highlights

Alzheimer’s disease (AD) is the most common form of dementia and is characterized by the presence of amyloid plaques and neurofibrillary tangles in brain tissue (Masters et al, 2015)
We wanted to confirm whether the enhanced mitochondrial transport found previously in 8e11 months homozygous MAPTP301L tau knockin mice (Gilley et al, 2012) was present in younger, 3-month-old homozygous tau knockin mice, an age when TgCRND8 shows substantial axonal swellings and an increasing plaque density (Adalbert et al, 2009)
We found that the number of CFP-labeled mitochondria moving in an anterograde direction was significantly higher in MAPTP301L/P301L mice relative to wildtypes (Fig 1A)

Summary

Introduction

Alzheimer’s disease (AD) is the most common form of dementia and is characterized by the presence of amyloid plaques and neurofibrillary tangles in brain tissue (Masters et al, 2015). Axonal transport is impaired in several amyloid and tau mouse models, and further impairment of transport increases pathology (Adalbert and Coleman, 2013; De Vos et al, 2008; Millecamps and Julien, 2013). These include transgenic mouse models overexpressing amyloid precursor protein (APP) or familial Alzheimer’s disease (FAD) mutant APP (Salehi et al, 2006; Stokin et al, 2005), mutant presenilin-1 (Lazarov et al, 2007), and wild-type and frontotemporal dementia with parkinsonism (FTDP) mutant tau (Ishihara et al, 1999; Zhang et al, 2004). We have reported live imaging of peripheral nerve explants of mitochondrial transport in a MAPTP301L/P301L knockin mutant mouse and in normal aging (Gilley et al, 2012; Milde et al, 2015)

Methods

Results

Conclusion