541 how tau and β-amyloid might collaborate to spark the cellular devastation of Alzheimer's disease (AD). The findings suggest that the two rogue proteins team up to break down the microtubules that enable neurons to deliver necessities to their axons.
AD's hallmarks are β-amyloid plaques that pile up outside of neurons and tangles of tau that amass inside. How the two proteins interact remains mysterious, but previous work indicates that β-amyloid lies upstream of tau in the cell damage pathway.
To clarify the connection, King et al. engineered kidney cells to pump out tau. In neurons from AD patients, microtubules collapse. The researchers saw the same effect when they dosed their engineered kidney cells with Aβ42, a particularly destructive version of β-amyloid.
Individual β-amyloid molecules can link together into long, tough fibrils that are prevalent in plaques. The cells were impervious to this fibrous form of β-amyloid, however, supporting the hypothesis that fibrils represent the brain's attempt to incarcerate ruinous β-amyloid.
Aβ42 also triggered microtubule breakdown in neurons, but not if the researchers first blocked tau with RNAi. The scientists now want to decipher how β-amyloid prods tau to do its bidding to cause microtubule collapse. Breaking down microtubules might harm neurons by interfering with the transport of essential cargo into axons and delivery of patches to fill gaps in the cell membrane.