Investigation of therapeutics that reduce tau accumulation through stimulation of autophagy in cell and rodent models.

2014  -  New York, NY, USA

Organizations

Columbia University

Supervising Advisor: Dr. Wai Huang Yu

Project summary:

Among the many human neurodegenerative disorders, there seems to be one common culprit – the abnormally high accumulation of aberrant or misfolded proteins. Alzheimer’s disease (AD) is associated with the buildup of b-amyloid and tau, which form toxic aggregates. Multiple studies have linked dysfunctional intracellular degradation with AD pathology. One such pathway is autophagy, which involves the delivery of large or long-lived protein aggregates and organelles to the lysosomes for enzymatic digestion.

Here we aimed to investigate potential therapeutics that reduce the build-up of tau through stimulation of autophagy in cell and rodent models. Our previous studies and others have shown that treatment with trehalose, a naturally-occurring sugar produced in plants and invertebrates, can activate autophagy and reduce tau aggregation in transgenic mouse models of AD. Despite these promising findings, trehalose is not an ideal therapeutic since it is a sugar and its chemical structure does not lend itself to the types of modifications necessary for drug development. Therefore, we aimed to uncover signaling pathways that are activated by trehalose and are able to promote clearance of tau aggregates by stimulating autophagy as new targets for drug discovery.

We treated cells that are prone to producing high levels of tau aggregates with trehalose. As expected, trehalose treatment increased levels of autophagy proteins. Our preliminary experiments suggest that trehalose activates AMP-activated protein kinase (AMPK). In a follow-up study, we treated cells with AMPK activator, metformin, to test whether promoting AMPK can elevate autophagy markers and reduce tau.

During the past year, we have also developed research tools to study the effects of impaired autophagy in transgenic mice with high levels of tau aggregates. We are currently constructing viruses that are capable of reducing gene expression of an essential autophagy protein in certain regions of the brain.