Mass General Researchers Link High Calcium Levels in Mitochondria to Neuronal Death in Alzheimer’s Disease

For the first time, using a mouse model of Alzheimer’s disease, scientists have documented a link between raised levels of calcium in mitochondria and neuronal death in the living brain. This relationship was previously documented in cell culture, but seeing this phenomenon in living mice makes it more likely that this occurs in people also and could point to a new target for Alzheimer’s disease.

“We were able to show mitochondrial calcium dysregulation in the neurons of living mice with Alzheimer’s-like symptoms using cutting edge live imaging techniques,” says the lead author of the paper, Maria Calvo-Rodriguez, PhD. The senior author is Brian J. Bacskai, PhD. They are both from the Department of Neurology at Massachusetts General Hospital.

Their collaborators included researchers from Harvard School of Public Health and the School of Medicine at Instituto de Investigacion Biomedica de Cadiz (INIBICA) in Spain. This study was recently published in Nature Communications.

One of the defining hallmarks of Alzheimer’s disease is the deposition of amyloid beta (Aβ) plaques and loss of neurons. The accumulation of Aβ has long been thought to be a trigger of the disease, but the exact means by which neurons die in Alzheimer’s remain a mystery, and the Aβ theory has become controversial because so many drug candidates targeting Aβ have failed in clinical trials.

One of the effects of Aβ plaques is that they cause high calcium ion (Ca²⁺) levels in the brain cells. There is also evidence that, at least in cell culture, exposure to Aβ can raise Ca²⁺ levels within mitochondria and lead to neuronal death. Mitochondria influence Ca²⁺ signaling inside neurons through the “mitochondrial calcium uniporter” that takes up Ca²⁺ into mitochondria. The investigation of this mechanism in living mice has been hampered by the lack of technologies sensitive enough to directly assess Ca²⁺ levels in mitochondria in the living brain.

To explore the relationship between Ca²⁺, mitochondria and neuronal death, Calvo-Rodriguez and her colleagues combined multiphoton microscopy with a ratiometric Ca²⁺ indicator targeted to mitochondria to asses Ca²⁺ levels. They applied these technologies to examine the neurons of a transgenic mouse model of Alzheimer’s disease that develops amyloid plaques similar to those from human patients.

Their studies demonstrate that increased mitochondrial Ca²⁺ levels are associated with plaque deposition and neuronal death in this model, indicating that abnormal Ca²⁺ levels in mitochondria could play a role in neuronal cell death in Alzheimer’s disease.

Additionally, they observed that when soluble Aβ is applied to the healthy mouse brain Ca²⁺ concentration in mitochondria increases. That process can be prevented by blockage of the mitochondrial calcium uniporter with a drug. Soluble Aβ is a type of Aβ similar to that in the human Alzheimer’s brain.

“High calcium levels in the mitochondria cause oxidative stress, and the death of neurons via apoptosis,” says Calvo-Rodriguez. “We propose that by blocking the neuronal mitochondrial calcium uniporter we can prevent cell death and impact disease progression.” Their work suggests targeting calcium entry to the mitochondria could be a promising new therapeutic approach in Alzheimer’s disease.

Funding: This work was supported by NIHR01AG0442603 (BJB) and a Tosteson & Fund for Medical Discovery postdoctoral fellowship (MCR). MSBB study was supported by the grants AG046170, AG054014, AG057440 and AG057907 from the NIH/National Institute on Aging (NIA). A.S.-P. was supported by the Alzheimer’s Association (AACF-17-524184) and the National Institute for Neurodegenerative Diseases and Stroke (NINDS R25NS065743). The ROSMAP project was supported by funding from the National Institute on Aging (AG034504 and AG041232). We acknowledge the Schepens Eye Research Institute Gene Transfer Vector Core for vector production.

Paper Cited: Calvo-Rodriguez, M., Hou, S.S., Snyder, A.C. et al. Increased mitochondrial calcium levels associated with neuronal death in a mouse model of Alzheimer’s disease. Nat Commun 11, 2146 (2020).

About the Massachusetts General Hospital

Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The Mass General Research Institute conducts the largest hospital-based research program in the nation, with annual research operations of over $1 billion and comprises more than 9,500 researchers working across more than 30 institutes, centers and departments. In August 2019, the Mass General was named #2 in the U.S. News & World Report list of "America’s Best Hospitals."