Targeting Tau With Antibodies in Alzheimer's Disease

Researchers here apply an immune therapy approach to clearing out misfolded or otherwise damaged tau proteins implicated in the pathology of Alzheimer's disease:

Tau aggregation occurs in neurodegenerative diseases including Alzheimer's disease and many other disorders collectively termed tauopathies. Trans-cellular propagation of tau pathology, mediated by extracellular tau aggregates, may underlie pathogenesis of these conditions.

P301S tau transgenic mice express mutant human tau protein and develop progressive tau pathology. Using a cell-based biosensor assay, we screened anti-tau monoclonal antibodies for their ability to block seeding activity present in P301S brain lysates. We infused three effective antibodies or controls into the lateral ventricle of P301S mice for 3 months.

The antibodies markedly reduced hyperphosphorylated, aggregated, and insoluble tau. They also blocked development of tau seeding activity detected in brain lysates using the biosensor assay, reduced microglial activation, and improved cognitive deficits. These data imply a central role for extracellular tau aggregates in the development of pathology. They also suggest that immunotherapy specifically designed to block trans-cellular aggregate propagation will be a productive treatment strategy.



I am sceptical. Hyperphosphorylated tau aggregates inside neurons to form neurofibrillary tangles, one of the traditionally accepted markers for Alzheimer's disease. It is not yet clear whether tangles cause neurodegeneration (the tau hypothesis) or are a product of damage or are neuroprotective. Therefore it is moot whether stopping the process of tangle formation or clearing the tangles would help or hinder suffers of this terrible disease.

As antibodies are ineffective inside the cell, this study targets extracellular tau. Success is claimed not only with some clearance but, more significantly, with reducing cognitive deficit. My scepticism is fuelled by the fact that the principal author of the paper, David Holtzman, is a cofounder of C2N Diagnostics and his University owns this company.

Posted by: richard at January 16th, 2014 8:13 AM

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