Break and accelerator-The mechanics of Tau (and amyloid) toxicity

Cytoskeleton (Hoboken). 2023 Aug 26. doi: 10.1002/cm.21781. Online ahead of print.


Aggregates of the microtubule-associated protein Tau define more than a dozen primary tauopathies, and together with amyloid-β, the secondary tauopathy Alzheimer's disease (AD). Historically, Tau has been viewed as executor of amyloid-β toxicity, with the two molecules working together as "trigger and bullet." Given the two protein's opposing roles in protein translation, we wish to introduce another metaphor, borrowing from the mechanics of a car, with amyloid-β boosting Tau translation, whereas Tau puts a break on global translation. The underlying studies entail an alternative hypothesis regarding Tau's subcellular accumulation in AD, namely its de novo synthesis in the somatodendritic domain rather than the relocalization from the axon upon dissociation from microtubules. We contest that it may be worth (given Tau's 50th birthday) to revisit some entrenched dogmas about Tau's pathophysiology.

Keywords: Alzheimer's disease; Frontotemporal dementia; amyloid; protein translation; tau.