In the Alzheimer’s brain, tau dissociates from microtubules, becomes hyperphosphorylated, and aggregates into neurofibrillary tangles. What kicks off this process? In the October 6 Neuron, researchers led by
In the Alzheimer’s brain, tau dissociates from microtubules, becomes hyperphosphorylated, and aggregates into neurofibrillary tangles. What kicks off this process? In the October 6 Neuron, researchers led by Huda Zoghbi and Juan Botas at the Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston, indict a new suspect. The kinase Nuak1, which structurally resembles AMP-activated protein kinase (AMPK), phosphorylates serine 356 in tau’s microtubule-binding domain, and this modification prevents tau degradation, causing levels to build up in the cytoplasm. That in turn triggers hyperphosphorylation, the authors report. Cutting Nuak1 levels in half in a tauopathy mouse model ameliorated pathology, restored normal synaptic plasticity, and improved memory. The findings point toward a new strategy for tackling tau accumulation, Zoghbi suggested.
Others agreed. “Therapeutic targeting of AMPK-related kinases … may offer a new way to combat AD and related tauopathies, for which there are currently no effective treatment options,” Bingwei Lu at Stanford University, Palo Alto, California, wrote to Alzforum. Franck Polleux at Columbia University, New York City, called the paper exciting. “The authors present strong evidence that Nuak1 is an important tau kinase, and may be a promi