Marisa Peryer, Senior Photographer

New research by Yale’s Nairn and Arnsten labs found that age-related Alzheimer’s disease is caused by the dysregulation of calcium in the brain. 

The study was published on April 7 in The Journal of the Alzheimer’s Association, and describes the mechanism behind late-onset Alzheimer’s disease. The researchers used the brains of monkeys to look at the pathology of Alzheimer’s disease and how aging increases one’s risk of developing the illness. The paper found that aging can cause the loss of proteins that regulate calcium, leading to the development of Alzheimer’s disease.

“The overall motivation was to look to see how normal aging may influence cellular events in the brain that ultimately result in the type of Alzheimer’s disease,” Angus Nairn, a professor of psychiatry at the Yale School of Medicine and one of the senior authors on the paper, said.

According to the study, there are two types of Alzheimer’s disease. In early-onset Alzheimer’s, which is the rarer form the disease, the illness is caused by genetic mutations. In late-onset sporadic Alzheimer’s, the cause of the disease is unknown, though this version of the disease is much more prevalent, the paper explained.

According to Dibyadeep Datta, a researcher in the Arnsten lab and the first author on the paper, aging is a strong risk factor for late-onset Alzheimer’s.

“Aging is by far the number one risk factor,” Datta said. “But why is that the case? To answer this question, we started probing at a much more cellular and molecular level to see what goes awry in the normal disease process.”

Datta explained that Alzheimer’s disease impacts specific parts of the brain important for cognition and episodic memories. By studying the cellular and molecular basis for the neuropathology of the disease, the researchers hoped to see what made these parts of the brain vulnerable, and how this could be rectified in order to prevent the disease from progressing, he said.

According to Amy Arnsten, a professor of neuroscience and the other senior author on the paper, the pathology of late-onset Alzheimer’s is characterized by abnormal phosphorylation of proteins, which is when a phosphate group is added to a protein to change its functions. The pathology of late-onset Alzheimer’s disease is hard to study in humans because by the time researchers acquire the brain from a cadaver, the phosphorylation state has been degraded.

Arnsten explained that although looking at human brains was not practical for the researchers, old rhesus monkeys develop the pathology of Alzheimer’s and can be acquired fast enough to observe.

“With monkeys, we can usually look at the brains quite quickly after they die,” Arnsten said. “We’re able to see these pathological phosphorylation states on these very old monkey brains, and we can figure out what’s happening to cause the pathology.”

According to Arnsten, the researchers found that cortical circuits, which are a part of the brain responsible for thought and awareness, involve calcium — an ion that is essential for many physiological functions. Near neural synapses, a high concentration of calcium is necessary for the cells to generate action potentials, which allow them to communicate to one another.

Arnsten explained that, while high levels of calcium are necessary in these locations, they must also be kept under tight control and otherwise can lead to toxic actions. According to Arnsten, the study showed that dysregulation of calcium correlates very strongly with the phosphorylation of the protein tau.

Aggregates of phosphorylated tau proteins, which are known as neurofibrillary fibers, are a primary biomarker of Alzheimer’s, according to the National Institute on Aging. In normal neurons, tau stabilizes microtubules, or structural components of cells. But when tau is phosphorylated, it binds other tau molecules, creating threads that become tangled. These tangles block the neuron’s transport system and impede communication between neurons.

“In this paper, we see a loss of the proteins that regulate calcium,” Arnsten said. “In a healthy young brain, the protein calbindin binds to calcium and keeps it from causing havoc, while phosphodiesterases chew up cyclic AMP, which signals calcium release. These two proteins are gone with age in these special, vulnerable neurons.”

According to Datta, the hope is that by understanding the origins of this dysregulation process, treatments that restore regulation and slow or stop pathology could be developed. Datta explained that individuals would have to start these treatments around middle age, as there is evidence that calcium dysregulation begins early in some of the circuits.

One of the next steps in this type of research is to understand what mediates tau phosphorylation,  Datta explained. Once the workings of tau phosphorylation are identified, the researchers can look for tools to suppress tau phosphorylation so communications between neurons are not disrupted.

According to the Alzheimer’s Association, people who are 65 and above survive an average of four to eight years after being diagnosed with the disease.

Kaitlin Flores |