Calcium channel blockers may be effective in treating memory loss in Alzheimer's disease
September 11, 2019
Science Daily/University of Bristol
Alzheimer's disease (AD) is the most common cause of dementia but the changes in brain cell function underlying memory loss remains poorly understood. Researchers at the University of Bristol have identified that calcium channel blockers may be effective in treating memory loss.
The team's findings, published in Frontiers in Cellular Neuroscience, found 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.
The researchers used fruit flies to study AD, using a fluorescent molecule called GCaMP6f, which reports the amount 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. 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.
The research team also investigated the memory of fruit flies by testing if they could remember which of two odours 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.
Dr James Hodge, Associate Professor in Neuroscience in the School of Physiology, Pharmacology & Neuroscience, said: "Memory loss in Alzheimer's disease (AD) is a highly distressing and difficult to treat symptom. Targeting the early changes in brain cell function -- before they begin to degenerate -- may be effective in treating memory loss.
"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."
In humans suffering with 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.
https://www.sciencedaily.com/releases/2019/09/190911101601.htm
New target regulating mitochondria during stress
Discovery could lead to new approach to treating heart failure, heart attack, stroke and neurodegeneration
September 19, 2019
Science Daily/Temple University Health System
Like an emergency response team that is called into action to save lives, stress response proteins in the heart are activated during a heart attack to help prevent cell death. As part of this process, Lewis Katz School of Medicine at Temple University researchers show for the first time that one of these specialized emergency responder proteins, known as MCUB, temporarily decreases harmful levels of calcium transport into mitochondria, the energy-generating batteries of cells.
The new research, published online September 19 in the journal Circulation, identifies MCUB as a promising new target for the investigation and treatment of conditions that feature calcium overload and cell death -- conditions that include heart failure, heart attack, stroke, and neurodegeneration.
"MCUB fine-tunes calcium uptake by mitochondria in injured heart tissue, in an attempt to limit calcium overload, which is a major contributor to cell death, particularly following a heart attack," explained John W. Elrod, PhD, Associate Professor in the Center for Translational Medicine at the Temple University Lewis Katz School of Medicine and senior investigator on the new study.
Calcium homeostasis is vital to a number of day-to-day cellular activities and is regulated primarily by mitochondria. For calcium to enter mitochondria, it passes through a channel known as the mitochondrial calcium uniporter (MCU), which resides in the inner mitochondrial membrane where it stimulates the production of ATP, the energy currency of the cell. The amount of calcium that mitochondria take up is regulated by various components of this channel. While MCUB closely resembles the pore forming subunit, MCU, its precise role in calcium regulation is largely unknown, particularly in the context of disease.
Dr. Elrod's team found that deletion of the MCUB gene in cells results in a change in the proteins that make up the calcium channel and that are essential for controlling whether the channel is on or off. Since these alterations are induced by stress, such as heart cell injury, the researchers next investigated the role of MCUB after heart attack in mice. In mice that suffered heart attack, the research team observed significant elevations in MCUB gene expression and decreases in MCU and the gatekeeper of the channel, MICU1. When genetically expressed prior to inducing a heart attack in mice, MCUB altered the channel to reduce calcium overload in the injured heart, ultimately curtailing tissue injury.
Dr. Elrod's team also found that, while it can improve cell survival after heart injury, increased MCUB activity comes at the expense of mitochondrial energy production. "MCUB induction is a compensatory change," explained Dr. Elrod. Just like an emergency responder, MCUB moves in and tries to reduce cell death and aid cell survival -- however, the reduction in mitochondrial calcium uptake is also maladaptive and limits the cell's ability to increase energy during stress.
"MCUB presents us with a new molecular target for investigation," Dr. Elrod said. "It's unique in that it alters the stoichiometry of the channel and thereby presents a new mechanism which may be amendable to therapeutic manipulation. We think that modulating MCUB may allow us to tune down mitochondrial calcium uptake without completely inhibiting all energetic function."
It is hoped that follow-up studies defining the exact sites of molecular interaction will provide additional insight into how to target mitochondrial calcium overload in heart disease.
https://www.sciencedaily.com/releases/2019/09/190919080749.htm