Neurons run on calcium, which plays a dual role as a charge carrier and an intracellular messenger. Calcium signals regulate various developmental processes and have a key role in apoptosis, neurotransmitter release, and membrane excitability; calcium is also involved in memory formation, metabolism, and cell growth—making it quite the multitasker.

Now using animal models, researchers at the Yale School of Medicine have discovered that susceptible neurons in the prefrontal cortex develop a “leak” in calcium storage with advancing age. These findings pave a new path of understanding in Alzheimer’s disease and may lead to potential new strategies that may delay or prevent disease progression.

Their findings are published in the journal Alzheimer’s & Dementia, The Journal of the Alzheimer’s Association in a paper titled, “Age‐related calcium dysregulation linked with tau pathology and impaired cognition in non‐human primates.”

The leak leads to accumulation of phosphorylated, or modified, tau proteins which cause the neurofibrillary tangles in the brain that are a hallmark of Alzheimer’s.

“The relationship of tau phosphorylation to calcium‐cyclic adenosine monophosphate (cAMP)‐protein kinase A (PKA) dysregulation was analyzed in aging rhesus macaque dorsolateral prefrontal cortex (dlPFC) and rat primary cortical neurons using biochemistry and immuno‐electron microscopy,” wrote the researchers. “The influence of calcium leak from ryanodine receptors (RyRs) on neuronal firing and cognitive performance was examined in aged macaques.”

Calcium dysregulation has previously been used as a target for new drug development in Alzheimer’s disease.

“Altered calcium signaling with advancing age is linked to early-stage tau pathology in the neurons that subserve higher cognition,” explained corresponding author Amy Arnsten, the Albert E. Kent professor of neuroscience and professor of psychology and member of the Kavli Institute of Neuroscience at Yale University.

Not only do these neurons face a leak, but as these neurons age, they tend to lose a protein called calbindin, which mediates calcium absorption, and protects neurons from calcium overload.

The researchers observed that the aged monkeys naturally developed hyperphosphorylated tau, including AD biomarkers and early tau pathology markers that correlated with evidence of increased calcium leak.

“Calcium also regulated early tau phosphorylation in vitro. Age‐related reductions in the calcium‐binding protein, calbindin, and phosphodiesterase PDE4D were seen within dlPFC pyramidal cell dendrites. Blocking RyRs with S107 improved neuronal firing and cognitive performance in aged macaques,” noted the researchers.

“With age, these neurons face a double whammy, with an excessive calcium leak that initiates toxic actions, as well as diminished levels of the protectant, calbindin,” said Arnsten.

The prefrontal cortex is an important site for working memory function. Neurons in the prefrontal cortex require high levels of calcium to perform their cognitive operations, but the calcium must be tightly regulated. But as regulation is lost with age, neurons become susceptible to tau pathology and degeneration.

“Understanding these early pathological changes may provide strategies to slow or prevent disease progression,” Arnsten said.

“Dysregulated calcium signaling confers risk for tau pathology and provides a potential therapeutic target,” concluded the researchers.