Study reveals new therapeutic target in neurodegenerative disease

Tau proteins aggregate to neurofibrillary tangles in a neuron axon

Early-cognitive decline may result from a shift in the ratio of a protein sub-type in our brain cells triggering cell-loss, according to a new study.

The discovery, published in Scientific Reports, provides a new therapeutic target to prevent the onset of neurodegenerative diseases including dementia and Alzheimer’s.

It is the first study to examine the effects on nerve activity of altering the balance of a key protein known as tau. Elevated amounts of the protein, which accumulates and forms tangles in the brain, is a hallmark of both dementia and Alzheimer’s. Although tau is well documented as one of the main damaging processes behind these diseases, until now its role in early-cognitive decline has not been well understood.

The role of L-type calcium channels

In normal human brain cells, there are approximately equal amounts of the six subtypes of tau, comprising three grouped together as 4R-tau, and three as 3R-tau. Scientists believe when there is a shift in the ratio of 4R-tau subtypes, this increase has adverse effects resulting in early cognitive impairment. 

To test this theory, researchers from Bristol’s Schools of Physiology, Pharmacology and Neuroscience, and Biochemistry examined the 4R-tau subtypes in more detail, and the acute effects of shifting the balance of the different subtypes on brain cell nerve activity.

The team found that two 4R-tau subtypes increased the number of L-type calcium channels in brain cells. The effect was produced from a direct protein to protein interaction between tau and the calcium channel. 

This increase in the number of L-type calcium channels caused the brain cell’s activity to be dampened by an enhanced inhibitory response known as the slow after-hyperpolarisation (slow AHP).

The team showed that the effect in the hippocampus resulted from more calcium entering the neurons through L-type calcium channels, which supports existing evidence that nerve death in dementia is caused by calcium overload.

A new therapeutic approach

Their discovery shows the changes that occur in a hippocampal nerve during early cognitive impairment are changes that occur before the patient is finally diagnosed with dementia.

Professor Neil Marrion, Professor of Neuroscience at Bristol’s School of Physiology, Pharmacology and Neuroscience, and the study’s lead author, said: “Our exciting findings suggest that by preventing the direct interaction between 4R-tau subtypes and L-type calcium channels could be used as a therapeutic approach to prevent the onset of dementia.”

The study was partly funded by the British Heart Foundation (BHF) and with support from MSc students.

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