Alzheimer's Disease Research - Current Award

	Jiaqi Yao, M.D., Ph.D. Weill Medical College of Cornell University New York, NY Title: The Role Of Actin Cytoskeletal Pathology In Alzheimer's Disease Non-Technical Title: Abnormal Changes Of The Actin Cytoskeleton Play Crucial Roles In Alzheimer's Disease Mentor: M. Flint Beal, M.D. Joan and Sanford I. Weill Medical College of Cornell University Duration: April 1, 2009 - March 31, 2011 Award Type: Research Fellowship Award Amount: $100,000
Summary: To investigate mechanisms and consequences of abnormal alterations of the actin cytoskeleton, which may play critical roles in Alzheimer’s disease (AD) causes and development. The proposed project focuses on a field that is largely unknown and will help us to understand the pathological development of AD from a fresh point of view.

Details:

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by cognitive impairment. We propose to investigate the role of abnormalities in actin, a major structural protein in neurons, in the disease. Abnormal rod-like accumulations of actin can be seen in neurons in Alzheimer's disease brains. We will examine potential mechanisms that cause these rods to form and follow consequences of their formation. This area has not previously received significant attention, and these studies should provide a fresh point of view and new therapeutic targets.

1. We will test the mechanisms inducing abnormal changes of the actin cytoskeleton.

2. We will examine the significant consequences of the actin pathology.

Progress Updates:

In addition to beta-amyloid (Aβ) plaques and neurofibrillary tangles, Alzheimer's disease (AD) brains also contain Hirano bodies -- rod-shaped structures containing actin, a cytoskeletal structural protein, and cofilin, an actin-binding protein. Actin and cofilin play critical roles in neuronal function. During the period from April 1, 2009 to March 31, 2010, we used a transgenic AD mouse model to examine the involvement of cofilin in AD pathogenesis. We found increased levels of cofilin in our AD mice and primary neurons from these mice had cofilin-containing, rod-like structures resembling Hirano bodies. Overexpressing active cofilin protein in normal neurons was sufficient to induce formation of these rod-like structures. Exploring the genesis of these cofilin abnormalities, we found that microRNA 107 inhibits expression of cofilin, and that microRNA 107 levels are decreased in our AD mice. Of note, microRNA 107 is also decreased in human AD brain. Note that microRNAs are short gene products naturally found in cells of the body that bind to other genes to “silence” or reduce their protein expression.

These data suggest that deficiency of this microRNA contributes to increased expression of cofilin, leading to Alzheimer’s disease pathology. The findings are novel and important in several ways. First, this is the first time that abnormal cofilin protein levels have been shown in an AD mouse model. Second, microRNA involvement in the cofilin abnormality has never been reported anywhere else. Finally, our study provides an interesting new direction in Alzhiemier’s disease research, to further understand and potentially treat this devastating disease. In the future, gene therapy targeting, and increasing, microRNA 107 expression might reverse the cofilin pathology with rod-like structure deposits, and assist in recovering cognitive function.