Targeting the Tangles

Although the relative importance of β-amyloid plaques and tau protein tangles in the progression of Alzheimer’s disease has been the subject of much debate, early emphasis was placed on the development of drugs to block production of β-amyloid. Although such compounds were shown to improve cognition in transgenic mice, unfortunately results from clinical trials have been more equivocal. Focus is now shifting to therapies that target tau pathology and, in a recent study, researchers from the University of Pennsylvania have identified a compound that reduced cognitive deficits in mutant human tau transgenic mice.

In healthy nerve cells, tau proteins interact with tubulin to stabilize axonal microtubules and promote tubulin assembly into microtubules. In Alzheimer’s disease and other ‘tauopathies’, hyperphosphorylated and misfolded tau proteins form insoluble neurofibrillary tangles that deplete levels of soluble tau and lead to destabilization of the microtubules and neuronal dysfunction. The team had previously proposed using microtubule-stabilising anti-cancer taxanes such as paclitaxel to treat tauopathies, but these do not penetrate the blood-brain barrier sufficiently well. The Penn team has now shown that once weekly treatment of tau transgenic mice with the brain-penetrant microtubule-stabilising agent, epothilone D, for three months significantly improved microtubule density and axonal integrity and also reduced cognitive deficits without notable side-effects.

The study, which is published in the Journal of Neuroscience, suggests that brain-penetrant microtubule-stabilising drugs could provide a new strategy for treating Alzheimer’s disease.