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Updated: Nov 9, 2025

In Vitro Aggregation Assays Using Hyperphosphorylated Tau Protein
Published on: January 2, 2015
Age-related calcium dysregulation linked with tau pathology and impaired cognition in non-human primates
Dibyadeep Datta1, Shannon N Leslie2,3, Min Wang1
1Departments of Neuroscience, School of Medicine, Yale University, Connecticut, USA.
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.
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