Tau In A Wrong Place

Dezhi Liao, PhD
University of Minnesota (Minneapolis, MN)

Co-Principal Investigators

Karen Hsiao Ashe, MD, PhD
University of Minnesota
Year Awarded:
2009
Grant Duration:
April 1, 2009 to March 31, 2011
Disease:
Alzheimer's Disease
Award Amount:
$150,000
Grant Reference ID:
A2009304
Award Type:
Pilot
Award Region:
US Midwestern
Dezhi Liao, PhD

Abnormal Presence Of Tau Proteins In Dendritic Spines

Summary

We will test the novel concept that specific chemical modification drives unual targeting of Alzheimer’s-linked “tau” proteins to the dendritic spines of neurons. This targeting might provide a mechanistic link between amyloid and tauopathies, hallmarks of the Alzheimer’s disease (AD) process. Therefore, the successful completion of this project will provide a more complete mechanistic model for AD than available at present.

Details

Alzheimer's disease (AD) is the most common cause of dementia in the elderly, causing gradual memory impairment. What is the culprit for this gradual memory impairment then? The brain is composed of many living units, which are called neurons. Each neuron contains hundreds or thousands of tiny apparatus that are called dendritic spines. If the brain is a computer, and then these dendritic spines serve as numerous storage units like the hard drive or Compact Disc (CD) of typical computers. Two main culprits for the memory loss in AD are two types of proteins: amyloid beta and tau. The co-PI, Dr. Karen Hsiao Ashe, a famous AD scientist, has previously found that a very small change in tau proteins (changing one amino acid from Proline to Leucine) can cause profound memory deficits. In our preliminary studies, we found that this tiny change in the amino acids of tau proteins can drive tau proteins to dendritic spines (right to the memory storage units of the brain!). The proposed project will focus on finding out why these unwelcome guests (tau proteins) frequently go to dendritic spines in AD and how much damage these unwelcome guests can cause. By understanding why, we might be able to develop a novel drug for treating AD by finding a way to block these unwelcome guests from entering our privileged house, the dendritic spine.

Research Updates

An unsolved puzzle in Alzheimer's disease (AD) research is why functional deficits, including memory problems, can occur before the death of neurons and other forms of structural damages.  Drs. Dezhi Liao and Karen Hsiao Ashe determined that the likely culprit for these early functional deficits in AD is a protein called tau.  Normally, tau proteins act as structural stabilizers for the main nerve cell frame and rarely go into the tiny extensions where nerve communication takes place, called dendritic spines.  Under disease conditions, tau proteins are driven to the dendritic spines where they shouldn’t be located, causing memory deficits by impairing nerve cell communication.   This research highlights that dendritic spines are a place to study early stages of AD. A new drug may be developed to target this mislocalization of tau protein before irreversible structural damages occur to brain cells.    

Publications

Brian Hoover; Miranda Reed; Jianjun Su; Rachel Penrod; Linda Kotilinek; Marianne Grant; Rose Pitstick; George Carlson; Lorene Lanier; Li-Lian Yuan; Karen Ashe; Dezhi Liao (2010) Tau mislocalization to dendritic spines mediates synaptic dysfunction independently of neurodegeneration. Neuron. 2010 Dec 22;68(6):1067-81. PubMed Icon Google Scholar Icon

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