Cognitive Impairment from Neurodegenerative Diseases May Be Reversible

Scientists in a recent study discovered a potential therapeutic target for patients with tauopathies. This group of neurodegenerative diseases are characterized by the aggregation of the tau protein in the brain.

Alzheimer’s disease is included in this group, since the tau protein aggregates inside of human brain cells. Normally, tau carries nutrients and other necessary materials inside brain cells and neurons. However, when this protein malfunctions and becomes toxic, it tangles and stops transporting materials, which leads to cell death and impairment.

A study published in Nature Medicine found that the cutting of tau by the enzyme caspase-2 may play a crucial role in impaired brain circuit function. The scientists also discovered that the tau fragment created by the cutting of the protein is resistant to creating aggregates, and initiates memory loss in animals prior to brain cell death.

Scientists were able to restore learning and memory deficits in mouse models of human tauopathy by inhibiting the activity of caspase-2, which suggests that some of the cognitive impairment could be reversed in humans.

“The results of this exciting study suggest that the cognitive loss that occurs in tauopathy may be reversed by blocking the function of caspase-2,” said Roderick A. Corriveau, PhD, a program director at the National Institute of Neurological Disorders and Stroke. “This motivates further investigation of caspase-2 as a novel therapeutic target for dementia.”

Scientists created a mouse model of tauopathy that produced a mutated version of human tau, and discovered that memory deficits were associated with the presence of the fragmented protein, according to the study.

This fragment is the result of caspase-2 cutting the tau protein at a specific location, and high levels of this protein fragment were found in patients with Alzheimer’s disease.

These findings may suggest that tau tangles may not be causing cognitive deficits, and tau fragments may play a larger role in the diseases.

“In the past, many studies focused on the accumulation of tangles and their connection to memory loss, but the more we learn, the less likely it seems that they are the cause of disease symptoms,” said senior author of the study Karen H. Ashe, MD, PhD. “The pathological fragment of tau that we have identified resists forming tangles and can instead move freely throughout the cell. Therefore, we decided to look for other mechanisms that could affect synaptic function.”

The scientists also used fluorescent labeling to track the behavior of mutated tau and compared it with mutated tau in cultured neurons from the hippocampus of rats.

Mutated tau and the tau fragment were discovered within dendritic spines, which is where neurons receive signals from nearby cells. An overabundance of mutated tau and the fragment were associated with a disruption in synaptic function in the spines, according to the study.

This was not seen to impact the structure or survival of neurons. The scientists are now planning to conduct experiments to determine how mutant tau causes memory deficits.

“It appears that abnormally processed tau is disrupting the ability of neurons to properly respond to the signals that they receive, producing memory deficits independent of tangle formation,” Dr Ashe said. “Because this effect is occurring without cell death or a loss of synapses, we have a better chance of intervening in the process and hopefully reversing symptoms of the disease.”