Building a Tau Immunotherapy that does not Increase Inflammation

Alzheimer's disease is associated with the aggregation of misfolded amyloid-β and tau proteins. The consensus position is that these aggregates are the primary cause of pathology, though the biochemistry involved is exceedingly complex and still being mapped. A sizable faction in the research community is working on immunotherapies to clear out misfolded amyoid, tau, or both, though so far this has proven to be more challenging than hoped. One of the potential issues is the risk of such a therapy generating greater inflammation in a patient whose condition is already inflammatory. This article gives an overview of one line of research into tau immunotherapies, and notes a recent step forward towards solving the inflammation problem:

The tangled buildup of tau protein in brain cells is a hallmark of the cognitive decline linked with Alzheimer's disease. Antibodies have been shown to block tau's spread, but some scientists worry it could also fuel inflammation. Now, researchers have found that an antibody's ability to recruit immune cells - known as its effector function - is not necessary for stopping tau's spread. Alzheimer's disease causes a characteristic constellation of pathologies: accumulation of amyloid-β plaques outside neurons, neurofibrillary tangles of tau inside brain cells, and chronic inflammation. Clinical research has mostly focused on targeting amyloid-β with antibody therapies, and several treatments based on this approach are currently in clinical trials. But recent efforts have zeroed in on tau as a new potential target.

Antibodies are known to spur the brain's defense system, microglia, to absorb and degrade tau, but their recruitment of immune cells may also worsen inflammation. Researchers wondered whether effector function was necessary for stopping tau's spread. To find out, the researchers raised transgenic mice that develop a tau pathology similar to that seen in Alzheimer's disease. The team treated the animals with antibodies that had either strong effector function or none at all. The animals that received antibodies with no effector function were able to clear tau as effectively as those that received full-effector function antibodies. "Low and behold, we don't need effector function in order to achieve a halting of accumulation of tau pathology." The findings suggest the antibodies could have an indirect effect on microglial activation, and may be unnecessary for therapeutic effect. The findings are likely to reignite an ongoing debate in the field over whether antibodies target tau inside or outside brain cells.



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