The Role Of Actin Cytoskeletal Pathology In Alzheimer's Disease

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.