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

Area of Science:

• Neuroscience
• Neurodegenerative Diseases
• Molecular Biology

Background:

• Axonal transport deficits are implicated in Alzheimer's disease (AD) and frontotemporal dementia (FTD).
• Stimulating axonal transport is a largely untested therapeutic strategy for neurodegenerative conditions.
• Previous work showed enhanced mitochondrial anterograde axonal transport in MAPT P301L knockin mice.

Purpose of the Study:

• To investigate if enhancing axonal transport in young TgCRND8 mice, a model for familial Alzheimer's disease, can alleviate axonal swelling.
• To characterize mitochondrial axonal transport in young MAPT P301L mice crossed with TgCRND8 mice.
• To determine the interaction between mutant tau and amyloid precursor protein (APP) mutations on axonal transport.

Main Methods:

• Utilized MAPT P301L knockin mice crossed with TgCRND8 mice to model combined tauopathy and amyloid pathology.
• Assessed anterograde axonal transport of mitochondria in young double-transgenic mice.
• Quantified plaque-associated axonal swellings and amyloid plaque load in the brains of TgCRND8 mice.

Main Results:

• Replicated enhanced anterograde axonal transport in young MAPT P301L/P301L knockin mice.
• Observed impaired anterograde axonal transport in MAPT P301L/P301L mice carrying APP mutations.
• Found no significant alteration in plaque-associated axonal swellings or amyloid plaque numbers in TgCRND8 brains.
• Amyloid-beta appears to promote an action of mutant tau that impairs axonal transport.

Conclusions:

• Amyloid-beta may exacerbate the detrimental effects of mutant tau on axonal transport.
• The interplay between amyloid-beta and mutant tau is critical in the pathogenesis of neurodegenerative diseases.
• Age-related increases in amyloid-beta could contribute to cognitive decline in FTD and AD.