Tangled Up in Tau
But the timing of treatment appears to be crucial. When Eva-Maria Mandelkow used methylene blue to treat mice that were 13 months old (the equivalent of about 40 years in humans) and had severe memory deficits, they didn’t improve. But when she gave the drug at nine months, just before the mice were starting to develop tau tangles and neuron loss, their memory and cognition were restored. “As long as you start before you have real cognitive decline, you have a chance to combat the memory loss,” she says. “Individuals who have a mutation in the tau gene may have pathology for 65 years and are fine until they suddenly develop cognitive decline. Apparently the brain can cope with these aggregates for many years. So maybe it’s not too late for someone who has mild cognitive impairment.”
Other researchers believe that the window of therapeutic opportunity comes when tau problems are localized in one part of the brain and before symptoms arise. This is a time when immunotherapy—an approach that has been tried, unsuccessfully, to treat Alzheimer’s disease—might work to prevent widespread neurodegeneration. “Many studies with immunization against tau have shown beneficial effects in mouse models of tauopathy,” says Goedert.
Despite all of the advances that have been made in understanding tau, much more needs to be learned. “There is a vibrant debate about whether tau aggregates are the most toxic or if we should be going after oligomers, a pre-filament form of tau, or soluble tau fragments,” says Hyman.
But neither soluble nor insoluble forms of abnormal tau are good. “It’s like asking whether you’d rather have toxins all over your neighborhood or piled together in a toxic waste dump at the end of the block,” he explains. Emerging research may conclude that attacking a form of tau other than tangles is more effective. Yet the important point is that a clear therapeutic target now exists. “We have shifted away from trying to fix impaired memory in Alzheimer’s disease or eye movement problems in progressive supranuclear palsy,” says Hyman. “Now we’re focused on the cause, which clearly involves tau.”