Blocking a harmful buildup of calcium inside the brain’s energy-producing mitochondria may hold the key to slowing Alzheimer’s disease, according to a new study from researchers at the Lewis Katz School of Medicine at Temple University.
The findings, published May 22 in the journal EMBO, identify mitochondrial calcium overload in neurons as a key driver of Alzheimer’s progression. Moreover, reducing neuronal calcium uptake prevents the accumulation of harmful proteins in the brain, helping protect against cellular damage and memory loss in experimental models of Alzheimer’s disease, pointing to a new target for future therapies.
“Our study provides strong evidence that excess calcium within mitochondria is not just associated with Alzheimer’s disease — it is actively contributing to the disease process,” said John W. Elrod, PhD, Director of the Aging + Cardiovascular Discovery Center (ACDC) and W.W. Smith Chair of Cardiovascular Medicine at Temple University’s Lewis Katz School of Medicine, and senior investigator of the study.
Alzheimer’s disease affects millions of people worldwide and remains one of the leading causes of dementia. Although current treatments can modestly improve symptoms for some patients, they do not stop the underlying neurodegeneration that drives progressive memory loss and cognitive decline.
For years, scientists have known that Alzheimer’s disease is associated with metabolic dysfunction, impairing the ability of cells to generate energy efficiently. Previous studies also suggested that abnormal calcium signaling may contribute to neuronal damage, but whether these processes are connected — and whether calcium overload in mitochondria directly drives disease progression — has remained unclear.
To investigate the question, Dr. Elrod and colleagues, led by postdoctoral fellow Pooja Jadiya, now an associate professor at Wake Forest University, genetically blocked a protein channel known as MCU, or the mitochondrial calcium uniporter, in neurons of mice engineered to develop Alzheimer’s-like disease. MCU acts as a gateway that allows calcium to enter mitochondria.
The results were striking. Mice lacking neuronal MCU showed significantly less accumulation of amyloid-beta and tau, the toxic proteins strongly associated with the development and progression of Alzheimer’s disease. The animals also demonstrated improved memory and learning abilities.
“We observed broad protection against disease progression,” Dr. Elrod said. “Neuronal activity and cognitive function improved even though the animals continued to express high levels of Alzheimer’s-associated genes.”
In particular, the researchers found that lowering mitochondrial calcium decreased oxidative stress, a damaging process caused by harmful, highly reactive oxygen-containing molecules. Excessive oxidative stress is suspected of contributing to neuronal injury and aging in Alzheimer’s disease.
The study also showed that reducing calcium overload restored autophagy, the cell’s natural waste-removal system. In Alzheimer’s disease, this process often becomes impaired, allowing toxic proteins and damaged cellular material to accumulate.
“When mitochondria become overloaded with calcium, neurons become overwhelmed trying to maintain energy production while clearing damaged mitochondria,” Dr. Elrod explained. “Preventing that overload preserved mitochondrial health, reduced the strain on the cell’s waste-removal system, and improved the clearance of toxic amyloid.”
Importantly, the findings suggest that mitochondrial calcium imbalance may occur early in Alzheimer’s disease, potentially well before cognitive decline.
This could help explain why many previous therapies targeting amyloid plaques alone have shown limited success. Most Alzheimer’s therapies have focused on clearing protein aggregates after the disease is already well underway. Targeting mitochondrial calcium dysregulation, which is further upstream in the disease process, can potentially slow progression before extensive neuronal loss occurs.
The findings build on earlier work from Dr. Elrod’s laboratory showing that impaired mitochondrial calcium removal contributes to age-related cognitive decline and Alzheimer’s disease progression. The next step is to identify safe drug-based approaches capable of modulating mitochondrial calcium handling in humans.
“There is still significant work ahead before this could translate into a therapy,” Dr. Elrod noted. “But these findings provide compelling proof-of-concept that mitochondrial calcium regulation represents a viable and potentially transformative therapeutic avenue for Alzheimer’s disease.”
As the global burden of Alzheimer’s disease continues to grow, the researchers hope the findings will encourage broader exploration of mitochondrial biology as a key factor in neurodegenerative disease.
“Alzheimer’s is an extraordinarily complex syndrome, and it will likely require new ways of thinking about treatment,” Dr. Elrod added.
Other researchers who contributed to the study include Elena Berezhnaya, Devin W. Kolmetzky, Dhanendra Tomar, Henry M. Cohen, Manfred Thomas, Salman Khaledi, Joanne F. Garbincius, Liam Kennedy Oniel Salik, and Alycia N Hildebrand, Aging + Cardiovascular Discovery Center, Department of Cardiovascular Sciences, Lewis Katz School of Medicine at Temple University, Philadelphia; and Shatakshi Shukla and Darpan Raghav, Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina.
The research was supported in part by funding from the National Institutes of Health, the Alzheimer’s Association, and the American Heart Association.