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

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 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.

Tau and Axonal Transport Misregulation in Tauopathies

“…Treatment of primary neurons with Aβ oligomers inhibited FAT of mitochondria and TrkA and the effect was dependent upon presence of tau [101]. A cross of MAPT P301L mice, an FTDP-17 tau line, with TgCRND8, a mouse line expressing mutant amyloid precursor protein, resulted in more severe decrease of mitochondrial transport while in the tau line alone aFAT was slightly increased before decreasing with age [1,26]. Synergistic effects of oligomeric Aβ have been noted in a variety of other studies as well.…”

Synergy between amyloid-β and tau in Alzheimer’s disease

“…Similarly, cross-breeding of the APPOSK model with wild-type tau mice (tau264 model) resulted in an earlier onset, enhanced HC synapse loss and spatial memory impairment, relative to the APP parental strain 74 . Other functional cellular impairments, such as defects in mitochondrial function and mitophagy (i.e., degradation of damaged mitochondria), as well as impaired axonal transport, have been observed in the presence of A and/or tau [75][76][77] , and the combination of A and tau has indicated synergistic effects in these cellular phenotypes [78][79][80] . Indeed, a synergistic reduction of mitochondrial membrane potential, ATP synthesis and respiration, as well as enhanced reactive oxygen species (ROS) production, was observed in APPxtau crosses (APP/PS2-pR5 model) when compared to each parent strain 81 .…”

The physiological roles of tau and Aβ: implications for Alzheimer’s disease pathology and therapeutics

“…Since the discovery of tau in 1975 [276], a plethora of research has focused on the role of tau at microtubules (reviewed in [10]). Microtubule deficits are common in AD and related disorders, with studies reporting axonal transport deficits [1], and defective microtubule assembly [115]. Tau binds tubulin via its microtubule-binding domains [141], with a single tau molecule crosslinking multiple tubulin dimers [6].…”

“…Knockdown of 4R tau in human induced pluripotent stem cell (iPSC)-derived neurons increases the velocity of mitochondrial transport [ 15 ]. Additionally, young P301L knockin mice, which exhibit reduced tau-microtubule binding, show enhanced anterograde transport [ 1 , 83 ]. It is hypothesised that tau may compete with motor proteins for tubulin-binding sites, and overexpression of tau has been reported to cause “traffic jams” [ 242 ] and induce kinesin dissociation from microtubules [ 61 , 65 , 233 , 255 ].…”