A biomarker for Alzheimer’s

Alzheimer’s disease (A.D.) is a neurodegenerative disorder that has no cure at present. But diagnosed early, its manifestations such as loss of short-term memory and decline in cognition can be delayed to a certain extent.

Now, a team of researchers from the Indian Institute of Science (IISc) in Bengaluru has identified a biomarker whose degradation they observed several years before clinicians noticed symptoms associated with the disease.

The molecule in question is a key protein in the brain called F-actin, or fibrillar actin. F-actin, a filamentous protein made of a large number of G-actins, is responsible for maintaining the shape of the mushroom-shaped projections called dendritic spines on the surface of a nerve cell. These protruding spines play a key role in communication between nerve cells. The scientists, belonging to the Centre for Neuroscience and the Centre for Brain Research at the IISc, found for the first time that F-actin is broken down early on in A.D., affecting the shape and number of dendritic spines.

For the current study, published recently in The Journal of Neuroscience, the IISc scientists genetically tweaked mice in such a way that they developed hereditary A.D. and looked for proteins that are involved in maintaining dendritic spine and their numbers. To their surprise, they found that the balance between F-actin and G-actin got disrupted in A.D.-induced mice, which were as old as one month. By contrast, the formation of toxic protein clumps called amyloid plaques, which is one of the first clinical symptoms, was typically seen only at seven to eight months of age in A.D. mice. To test whether F-actin loss had any effect on behaviour, the researchers designed experiments in which they trained the mice to fear a specific location or context by giving them a mild electric shock. When normal mice were placed in the same arena the next day, they froze, remembering and anticipating the shock. A.D. mice as young as two months old, however, did not freeze, indicating that they had forgotten the context.

Remarkably, when the researchers chemically blocked F-actin from breaking down, they found that the mice were able to regain their normal fear response. “That was very striking. When we stabilised the F-actin, we were able to see the behaviour recovery,” said Reddy Kommaddi, first author and D.B.T. Ramalingaswami Fellow at the Centre for Neuroscience. In the next set of experiments, when the scientists broke down F-actin using a chemical, they found that normal mice forgot their fear, just like the A.D. mice. “We deliberately depolymerised F-actin in normal mice and showed that this itself is enough for the deficit to manifest,” said Smitha Karunakaran, another author and scientist at the Centre for Brain Research. “Because F-actin is a structural protein, it gives shape to all cells in the body and is present everywhere. It could potentially become a biomarker,” said Vijayalakshmi Ravindranath, senior author and a professor at the Centre for Neuroscience.

T.V. Jayan