Age‐related calcium dysregulation linked with tau pathology and impaired cognition in non‐human primates

INTRODUCTION: The etiology of sporadic Alzheimer's disease (AD) requires non‐genetically modified animal models. METHODS: 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. The influence of calcium leak from ryanodine receptors (RyRs) on neuronal firing and cognitive performance was examined in aged macaques. RESULTS: Aged monkeys naturally develop hyperphosphorylated tau, including AD biomarkers (AT8 (pS202/pT205) and pT217) and early tau pathology markers (pS214 and pS356) that correlated with evidence of increased calcium leak (pS2808‐RyR2). Calcium also regulated early tau phosphorylation in vitro. Age‐related reductions in the calcium‐binding protein, calbindin, and in phosphodiesterase PDE4D were seen within dlPFC pyramidal cell dendrites. Blocking RyRs with S107 improved neuronal firing and cognitive performance in aged macaques. DISCUSSION: Dysregulated calcium signaling confers risk for tau pathology and provides a potential therapeutic target.