New insight and target for Alzheimer’s disease

The body is designed to fix anything that is out of balance. Homeostasis is maintained in the body, and even a minor change could trigger a compensatory mechanism, in the hopes of keeping everything stable. Sometimes, however, the effort of the body to fix a faulty part of the body could lead to unexpected effects. It’s just like when you try to fix a minor problem and instead of fixing it, worse things happen. The cells are the same, in many ways. They try to compensate for a minor dysfunction or deficiency but instead of keeping everything in balance, problems start to fire out.

In a new study published in the journal Nature Communications, a team of researchers at the Lewis Katz School of Medicine at Temple University (LKSOM) found that an attempt by the cells of the body to compensate a problem, could ultimately lead to declines in learning and memory, a hallmark sign of dementia, particularly Alzheimer’s disease (AD).

The research is the first to link maladaptive changes in calcium transport by mitochondria – the energy-generating powerhouses of cells – to the progression of Alzheimer
The research is the first to link maladaptive changes in calcium transport by mitochondria – the energy-generating powerhouses of cells – to the progression of Alzheimer's disease. Image Credit: Atthapon Raksthaput / Shutterstock

In the cells, mitochondrial calcium transport remodeling happens when the cells detect a problem. It is an attempt by the cells to compensate for flagging energy production and metabolic dysfunction. In the beginning, this compensatory mechanism is beneficial. However, in the long run, it could potentially lead to declines in mitochondrial function, learning, and memory.

First to link maladaptive changes to Alzheimer’s disease

The study is the first of its kind to link maladaptive changes in calcium transport by mitochondria, the cell’s powerhouses that produce energy, to the development and progression of Alzheimer’s disease.

"Amyloid-beta deposition and tau pathology are considered the major contributors to Alzheimer's disease and, as a result, they have been the main focus of therapeutic development," Dr. John Elrod, Associate Professor in the Center for Translational Medicine at LKSOM and lead author of the study, explained.

"Large clinical trials targeting these pathways have universally failed, however,” he added.

Alzheimer’s disease and calcium regulation link

Alzheimer’s disease (AD) is an age-associated multifactorial disease, which stems from to main pathological hallmarks – beta-amyloid plaque formation and neurofibrillary tangles in the brain. These brain changes trigger neurodegeneration, leading to memory loss and decline in cognitive skills.

Intracellular calcium signaling plays a pivotal role in synaptic transmission and neuronal intracellular and paracellular communication. Calcium regulation is viral in cellular homeostasis, and it’s not surprising that alterations in calcium handling could influence neurodegeneration and age-related diseases, including Alzheimer’s disease.

In the past, scientists have suspected that altered calcium regulation and metabolic dysfunction could lead to neuronal dysfunction and the development of dementia. However, there have been no studies to prove the hypothesis. No one has investigated the effect of altered calcium transport into and out of the cell mitochondria on the development and progression of AD.

Calcium transport into and out of the mitochondria plays a pivotal role in several cellular functions. But, the process requires many protein regulators, including NCLX. This protein is important in mitochondrial calcium efflux in nerve cells.

The team observed mice models in the laboratory to determine the role of calcium uptake in the mitochondria of neurons in AD. The mice models had AD with three gene mutations to provide a scenario similar to human patients. When the mice grew older, the team observed that there was a steady decline in NCLX expression, accompanied by reductions in protein expressions, limiting mitochondrial calcium uptake. As a result, a damaging calcium overload occurs, and the loss of NCLX was associated with an increase in the production of cell-damaging oxidants.

The team also tried to entirely remove NCLX expression in AD mice’s forebrain. When they tested for cognitive function and memory, the mice manifested marked impairments. Upon studying the brain tissue of these mice, the scientists found that there was a significant reduction in NCLX, followed by mitochondrial calcium efflux loss. All these events led to the formation of amyloid-beta and tau pathology.

Also, when the NCLX expression was restored, it led to improvements in cognitive ability and the neuronal mitochondrial calcium homeostasis was reinstated.

The study findings shed light on another potential cause of Alzheimer’s disease, paving the way for the development of noble treatments in the future.

Dementia affects around 50 million people worldwide. By 2050, the number is expected to rise to 115.4 million. Alzheimer’s disease is the most common type of dementia, affecting 5 million people in the United States alone in 2014, making it the 6th leading cause of death in the country.

Journal reference:

Jadiya, P., Kolmetzky, D., Tomar, D., Di Meco, A., Lombardi, A., Lambert, J., Luongo, T., Ludtmann, M., Pratico, D., and Elrod, J. (2019). Impaired mitochondrial calcium efflux contributes to disease progression in models of Alzheimer’s disease. Nature Communications.

Angela Betsaida B. Laguipo

Written by

Angela Betsaida B. Laguipo

Angela is a nurse by profession and a writer by heart. She graduated with honors (Cum Laude) for her Bachelor of Nursing degree at the University of Baguio, Philippines. She is currently completing her Master's Degree where she specialized in Maternal and Child Nursing and worked as a clinical instructor and educator in the School of Nursing at the University of Baguio.


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