A little extra calcium is a good thing, to help maintain healthy bones and muscles. However, too much calcium in your neurons could be an underlying cause of memory loss for those afflicted with Alzheimer’s disease (AD). Alzheimer’s is the most common cause of dementia, but the changes in brain cell function that mediate memory loss remain poorly understood. However now, researchers at the University of Bristol have identified that calcium channel blockers may be an effective way of treating memory loss.

Findings from the new study—published recently in Frontiers in Cellular Neuroscience through an article titled “Restoration of Olfactory Memory in Drosophila Overexpressing Human Alzheimer’s Disease-Associated Tau by Manipulation of L-Type Ca2+ Channels”—found that treating a diseased brain cell with a blocker of the L-type channel reduced the number of calcium ions able to flow into the brain cell.

“Memory loss in AD is highly distressing and a difficult to treat symptom. Targeting the early changes in brain cell function—before they begin to degenerate—may be effective in treating memory loss,” noted senior study investigator James Hodge, PhD, associate professor in neuroscience at the University of Bristol.

In the current study, the investigators used fruit flies to study AD, using a fluorescent molecule called GCaMP6f, which reports the number of calcium ions inside brain cells. They found that diseased brain cells become overloaded with calcium ions, which at normal levels are important for memory formation.

Treating diseased brain cells with calcium channel blockers: A diseased brain cell (middle) has more L-type channels, and consequently more calcium ions inside it, than a healthy brain cell (left). Treating the diseased cells with a blocker of the L-type channel reduced the number of calcium ions able to flow into the cell (right) [University of Bristol]
This overload was due to the overproduction of the gene encoding a channel, known as the L-type channel, which allows calcium ions to flow into the cell from outside. More of these channels means more calcium ions are able to flow into the cell, disrupting memory formation. Using a drug to block the L-type channel reversed the effect of disease and reduced the flow of calcium ions to a normal level.

“We utilized the tractable neural circuits sub-serving memory in Drosophila to investigate the role of impaired Ca2+ handling in memory deficits caused by expression of human 0N4R isoform of tau which is associated with AD,” the authors wrote. “Expression of tau in mushroom body neuropils, or a subset of mushroom body output neurons, led to impaired memory. By using the Ca2+ reporter GCaMP6f, we observed changes in Ca2+ signaling when tau was expressed in these neurons, an effect that could be blocked by the L-type Ca2+ channel antagonist nimodipine or reversed by RNAi knock-down of the L-type channel gene. The L-type Ca2+ channel itself is required for memory formation, however, RNAi knock-down of the L-type Ca2+ channel in neurons overexpressing human tau resulted in flies whose memory is restored to levels equivalent to wild-type. Expression data suggest that Drosophila L-type Ca2+ channel mRNA levels are increased upon tau expression in neurons, thus contributing to the effects observed on memory and intracellular Ca2+ homeostasis.”

The research team also investigated the memory of fruit flies by testing if they could remember which of two odors had previously been paired with an electric shock—similar to Pavlov’s experiments with dogs.

While healthy flies remembered well, the diseased flies, like humans, displayed impaired memory. However, if the overproduction of L-type channels was corrected in the diseased flies, their brain cells were no longer overloaded with calcium ions and their memory was just as good as healthy flies. This shows that memory loss is likely due to calcium overload because too many L-type channels are made and, if this is corrected, memory impairment is rescued.

“L-type channels have been thought to have a role in AD for some time and this study shows a direct link between memory loss and L-type channel overproduction in brain cells,” Hodge explained.

In humans suffering from AD, blocking these channels may be beneficial in treating memory impairment. The findings show that further work should be carried out to determine the mechanism underlying the recovery of memory and whether or not the team’s research will prove effective in humans.

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