Alzheimer's research—intracellular calcium store malfunction leads to brain hyperactivity

February 9, 2018, Universitaet Tübingen
Amyloid proteins (plaques, blue) in the cerebral cortex of a mouse model of Alzheimer’s disease, surrounded by cortical immune cells (microglia, green). Activated microglia cells (positive for CD-68) are marked red. Credit: O. Garaschuk/PNAS

Alzheimer´s disease is the key cause of dementia in elderly patients. Those affected develop deficiencies in their abilities to learn, think logically, communicate, and to master the challenges of everyday life. To find out more about how the disease comes about, researchers at the University of Tübingen used mice, developing the same amyloid protein deposits in their brains as human patients, and which also suffer memory loss. Several years ago, a team led by Professor Olga Garaschuk showed that in these mice, the disease coincided with a noticeable increase in nerve cell activity in the brain. There were similar findings in human Alzheimer's patients.

Now, Garaschuk's team at the University of Tübingen's Institute of Physiology can explain an important mechanism behind this neural hyperactivity in mice. At the contact points between cells, there is a malfunction in the intracellular storage which is needed for signal transfer. As a result, too many signal chemicals (neurotransmitters) are released into the synaptic cleft. The study, published in the latest edition of PNAS, shows how new findings can lead to fresh approaches to treatment of the hereditary form of Alzheimer´s disease.

Communication between nerve in the brain is largely carried out via electrical signals. But at the synapse – the transfer point between one nerve cell and another – the signal switches to a chemical one. Calcium plays an important role here; it helps to release messenger chemicals known as neurotransmitters. They dock onto the next nerve cell, where another electrical impulse is generated and sent on. In the new study, Garaschuk found that in mouse models of Alzheimer's disease showing this abnormal increase in brain nerve cell activity, calcium storage at the presynaptic side was dysregulated. "This releases a larger amount of neurotransmitters into the cerebral cortex – which leads to hyperactivity in the ," she explains.

Alzheimer's occurs sporadically in humans, the greatest risk factor being age. Yet a proportion of Alzheimer's patients also have a genetic tendency towards the disease. In this kind of Alzheimer´s, 90 percent of those affected have a mutation of the presenilin gene. "Interestingly, in mice, one single copy of this kind of mutated gene is enough to cause hyperactivity due to calcium storage malfunction," Garaschuk says. Chemical agents which can empty the cell's calcium storage or – as one clinically approved drug does – block the release of calcium from this store; they also suppress the cell hyperactivity. "That leads to a normalisation of functions," she says. These findings could play a role in the development of new treatments for Alzheimer's .

Explore further: Diabetes drug 'significantly reverses memory loss' in mice with Alzheimer's

More information: Chommanad Lerdkrai et al. Intracellular Ca2+stores control in vivo neuronal hyperactivity in a mouse model of Alzheimer's disease, Proceedings of the National Academy of Sciences (2018). DOI: 10.1073/pnas.1714409115

Related Stories

Diabetes drug 'significantly reverses memory loss' in mice with Alzheimer's

January 1, 2018
A drug developed for diabetes could be used to treat Alzheimer's after scientists found it "significantly reversed memory loss" in mice through a triple method of action.

Boosting a cell-protecting protein may help slow Alzheimer's disease progression

March 2, 2017
A new study of Alzheimer's disease by Fiona Kerr and Linda Partridge at University College London, uses mouse and fruit fly models to show that Keap1, which inhibits the protective protein Nrf2, is a promising target for ...

'Alzheimer protein' seems to slow down neurotransmitter production

August 21, 2012
Researchers report how abnormal protein deposits in the brains of Alzheimer's patients disrupt the signaling between nerve cells. They varied the amount of APP protein and related proteins associated with Alzheimer's disease ...

New light shed on early stage Alzheimer's disease

April 22, 2013
The disrupted metabolism of sugar, fat and calcium is part of the process that causes the death of neurons in Alzheimer's disease. Researchers from Karolinska Institutet in Sweden have now shown, for the first time, how important ...

Role of calcium in familial Alzheimer's disease clarified, pointing to new therapeutics

May 13, 2014
In 2008 researchers at the Perelman School of Medicine at the University of Pennsylvania showed that mutations in two proteins associated with familial Alzheimer's disease (FAD) disrupt the flow of calcium ions within neurons. ...

Antibiotic restores cell communication in brain areas damaged by Alzheimer's disease

November 15, 2016
New research from the Djavad Mowafaghian Centre for Brain Health at UBC has found a way to partially restore brain cell communication around areas damaged by plaques associated with Alzheimer's disease.

Recommended for you

What really causes Alzheimer's and how might we fix it?

May 23, 2018
There have been a lot of theories about what causes Alzheimer's disease. Many of them have given rise to experimental treatments of one form or another. None of them have worked much better than taking anything you might ...

Study predicts most people with earliest Alzheimer's signs won't develop dementia associated with the disease

May 22, 2018
During the past decade, researchers have identified new ways to detect the earliest biological signs of Alzheimer's disease. These early signs, which are detected by biomarkers, may be present before a person starts to exhibit ...

Moderate to high intensity exercise does not slow cognitive decline in people with dementia

May 16, 2018
Moderate to high intensity exercise does not slow cognitive (mental) impairment in older people with dementia, finds a trial published by The BMJ today.

Mutation discovered to protect against Alzheimer's disease in mice

May 16, 2018
Researchers at the RIKEN Center for Brain Science have discovered a mutation that can protect against Alzheimer's disease in mice. Published in the scientific journal Nature Communications, the study found that a specific ...

Most deprived are nearly twice as likely to develop dementia

May 16, 2018
Older adults in England with fewer financial resources are more likely to develop dementia, according to new UCL research.

Scientists discover a variation of the genome predisposing to Alzheimer's disease

May 15, 2018
An article published in Nature Medicine shows that the inheritance of small changes in DNA alters the expression of the PM20D1 gene and is associated with an increased risk of developing Alzheimer's disease.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.