The Role Of Actin Cytoskeletal Pathology In Alzheimer's Disease

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.

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 and cofilin (cell structure proteins). Actin and cofilin play critical roles in nerve function. Drs. Jiaqi Yao, Flint Beal, and colleagues found increased levels of cofilin in mice with AD, 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.

Dr. Yao and colleagues found two microRNAs that repressed the creation of cofilin in mice. microRNAs are short gene products naturally found in cells of the body that “silence” or reduce gene protein expression. Of note, one of these two microRNAs is also decreased in human AD brain. Dr. Yao showed in a mouse model of AD that brain levels of these two microRNAs are decreased, with corresponding increases in brain cofilin levels, and formation of cofilin-actin rods in nerve cells and brain sections. Overexpression of inactive cofilin does not induce rod formation.

These data suggest that deficiency of these microRNAs contribute to increased expression of cofilin, leading to Alzheimer’s disease. This is the first time that abnormal cofilin protein levels have been shown in an AD mouse model. In addition, this is the first report of microRNA involvement in cofilin abnormality.  In the future, gene therapy targeting to increase expression of both mRNAs might reverse the cofilin induction of rod-like structure deposits in the brain and perhaps contribute to cognitive recovery.