Jaya Padmanabhan, Ph.D.
Johnnie B. Byrd, Sr. Alzheimer's Center and Research Institute, Inc.
Tampa, Florida

2008 Investigator-Initiated Research Grant

The protein tau normally plays a vital role in maintaining the structural framework and transport system within brain cells. Tau is usually modified by phosphorylation, or the attachment of phosphate molecules. But excessive phosphorylation may prevent the protein from carrying out its normal functions and cause it to accumulate into neurofibrillary tangles. These tangles are pathological hallmarks of Alzheimer's disease.

In preliminary studies, Jaya Padmanabhan, Ph.D., and colleagues found that a protein called alpha 1-antichymotrypsin (ACT) may be associated with neurofibrillary tangles. The researchers found elevated ACT levels in autopsied brain tissue of people with extensive tangle formations. Moreover, in studies with mice engineered to overexpress ACT, these animals were found to develop elevated levels of excessively phosphorylated tau. Such observations suggest that ACT may play a vital role in the development of Alzheimer's disease.

Dr. Padmanabhan's team plans to conduct a more thorough investigation of the Alzheimer-related activities of ACT. For this effort, it will use both cultured cells and mice engineered to overexpress both human tau and human ACT. The researchers hope to learn more about the biological mechanisms underlying ACT's effect on tau phosphorylation. They suspect that other proteins, including glycogen synthase kinase 3, might assist ACT in this process.

The results of Dr. Padmanabhan's effort could shed new light on the mechanisms behind neurofibrillary tangle formation. Such knowledge could ultimately lead to more precise Alzheimer therapies.