Testing the Prospects for Therapies that Target Tau Protein

This popular science article looks at efforts to build therapies that target aggregations of tau, thought to contribute to neurodegenerative conditions such as Alzheimer's disease, but also present in a range of diseases known as tauopathies. Some tauopathies may in effect come to serve as testbeds for later efforts to treat Alzheimer's by clearing tau aggregates, because the link between tau and pathology is more clear in these conditions:

About 100 times rarer than Parkinson's disease, and often mistaken for it, progressive supranuclear palsy (PSP) afflicts fewer than 20,000 people in the U.S. This little-known brain disorder is quietly becoming a gateway for research that could lead to powerful therapies for a range of intractable neurodegenerative conditions including Alzheimer's and chronic traumatic encephalopathy, a disorder linked to concussions and head trauma. All these diseases share a common feature: abnormal buildup of a protein called tau in the brains of patients. People with PSP lose the sense of balance, although unlike in Parkinson's they fall backward instead of forward. Many PSP patients also struggle with speaking and swallowing. The problems can be traced to loss of nerve cells in the brain areas responsible for those capabilities - such as the basal ganglia, brain stem and cerebral cortex. Under a microscope these are the very regions that accumulate tangled clumps of tau, a normal protein found mostly in neurons. It binds to structures called microtubules, which help move nutrients up and down the cell. But in PSP and related disorders something goes wrong: Tau proteins twist out of shape and start sticking to one another rather than stabilizing microtubules. Then, through a mysterious process, the tau clusters leave the cell, spread throughout the brain and muck up communication between neurons.

Beyond PSP, other brain diseases are also marked by abnormal tau clumps. Research on Alzheimer's has focused largely on another protein called amyloid beta, which clusters into "plaques" in the brain. But there is growing interest in tau's role. When researchers analyzed healthy young adults, healthy older adults and older adults diagnosed with "probable Alzheimer's," those with a lot of tau in the temporal lobes and neocortex - brain areas important for sensory perception and memory - were close to dementia onset whereas symptoms could still be years out for people with high amyloid. Examining the brain scans in the context of other disease markers in the same participants showed that the rise and spread of tau in the brain tracked more closely with declining mental function than did amyloid. Location seems critical, too. Whereas amyloid may show up in various brain areas, tau appears more restricted to regions associated with the cognitive deficits.

Because tau more closely aligns with the start of dementia, an effective therapeutic has "probably got to deal with the tau." In past years researchers have identified tau-binding antibodies that slow the spread of toxic tau clusters in a lab assay using cultured cells. When injected into mice engineered with a tau mutation that makes the protein clump abnormally in brain cells, triggering memory and motor problems, the antibodies reduced the clumping and improved the animals' behavior. Other approaches aim to decrease tau protein production by targeting RNA; blocking tau clustering by interfering with chemical modifications on the protein's surface; or binding microtubules in order to enhance a normal tau function that gets lost as the protein misfolds and aggregates. At present a few tau-targeting approaches are being evaluated in Alzheimer's clinical trials. But more are being tested in people with PSP. Scientists are eager to assess tau therapies in PSP for a number of reasons: First, it is a pure tauopathy. Whereas people with Alzheimer's can have tau as well as several other proteins clustering in their brains, PSP patients only have abnormal tau. Second, tau has a stronger genetic link to PSP than it does to Alzheimer's. Other reasons for testing tau drugs in PSP patients have more to do with clinical trial practicalities. If an intervention is effective, then the participants taking the study drug should deteriorate more slowly than those in the placebo group. In some diseases such as Alzheimer's, however, decline is slow and inconsistent to begin with. PSP, by comparison, runs its course more rapidly and predictably.

Link: http://www.scientificamerican.com/article/obscure-disease-may-offer-backdoor-to-new-treatments-for-alzheimer-s-and-other-killers/

Comments

Just recently was diagnosed with PSP and am eager to find out anything, and try anything to combat this disease.

Posted by: John Clark at July 19th, 2016 1:37 PM

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