Journal
NEUROBIOLOGY OF AGING
Volume 68, Issue -, Pages 68-75Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.neurobiolaging.2018.03.033
Keywords
Axonal transport; Alzheimer's disease; FTDP-17T; P301L mutation; A beta; Mitochondria
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Funding
- Alzheimer's Research UK [ART/PG2009/2]
- MRC project [MR/L003813/1]
- Medical Research Council studentship
- Alzheimer's Research UK studentship [ARUKPhD2013-13]
- Biotechnology and Biological Sciences Research Council Institute Strategic Programme Grant
- Foundation for Alzheimer Research (FRA/SAO)
- Belgian F.N.R.S.
- BBSRC [BBS/E/B/000C0433] Funding Source: UKRI
- MRC [MR/L003813/1] Funding Source: UKRI
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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-beta promotes an action of mutant tau that impairs axonal transport. As amyloid-beta levels increase with age even without amyloid precursor protein mutation, we suggest that this rise could contribute to age-related decline in frontotemporal dementia. (C) 2018 The Authors. Published by Elsevier Inc.
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