Alzheimer's Disease Research - Completed Award

	Erin Congdon, Ph.D. Research Foundation For Mental Hygiene New York, NY Title: Tau Dissociation As A Therapeutic Approach For Tauopathy Non-Technical Title: Untangling Tau As An Approach To Treating Tangles In AD Mentor: Karen Duff, Ph.D. Columbia University Duration: April 1, 2009 - September 30, 2011 Award Type: Research Fellowship Award Amount: $100,000
Summary: Aggregated tau accumulated in tangles is a major feature of the Alzheimer’s disease affected brain. These accumulations are thought to be highly toxic to neurons. Aggregated tau can be disassociated in test tubes by several compounds including cyanine dyes. We aim to test the therapeutic potential of a cyanine dye both in living systems and in living system models of disease.

Details:

Tau is a protein that forms an abnormal mass of tangles inside the brain cells of patients with Alzheimer’s disease (AD). Tangled tau is thought to be highly toxic to neurons. Tangled tau in a test tube can be broken up by certain drugs. However, we do not know if any of these drugs work efficiently on real tangles in a living brain. We aim to test whether one particular compound that works in the test-tube is capable of detangling tau in a mouse model of AD. A successful outcome would pave the way for development of this compound as an anti-Alzheimer’s disease drug.

Publications:

Congdon EE, Figueroa HY, Wang L, Toneva G, Chang E, Kuret J, & Duff KE. (2009). Inhibition of tau polymerization with a cyanine day in two distinct model systems. J Biol Chem. 284(31):20830-9  

(This paper demonstrates the biphasic effect of cyanine C11 in slice and cell cultures. Results demonstrate that tau polymerization can be modulated directly without the need to alter phosphorylation. )

Duff, K, Kuret, J & Congdon, EE. (2010). Dissagregation of tau as a therapeutic approach to tauopathies. Curr Alzheimer Res. Epub ahead of print.  

(This paper summarizes results from two studies using C11 in culture. )

Progress Updates:

One of the defining features of Alzheimer's disease is the buildup of brain lesions containing polymerized, or tangled, Tau protein. Because these lesions correlate with disease progression, they represent a possible target for the development of disease-modifying therapies. Small molecules or chemicals have been identified which are capable of reducing tau polymerization or tangling. One of these is a cyanine dye, called C11. Our current project uses this dye in cell, tissue and animal models of disease. We have shown that C11 produces different effects as its concentration changes. At low doses, C11 reduces Tau protein polymerization in both cells and tissue culture models. However, at higher doses, Tau protein aggregation is promoted. This finding indicates that Tau is a valid target for drug development, but that testing over a wide variety of concentrations and in multiple model systems is essential. Finally, because C11 can both inhibit and promote Tau polymerization, it can also be used to test the effects of aggregate buildup on the health of the cell.