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

Alzheimers Dement. 2021 Jun;17(6):920-932. doi: 10.1002/alz.12325. Epub 2021 Apr 7.


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.

Keywords: PKA; aging; association cortex; calpain; impaired cognition; macaque; pyramidal cells; ryanodine receptor; tau.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / pathology
  • Animals
  • Calcium / metabolism*
  • Calcium Signaling
  • Cognitive Dysfunction / pathology*
  • Cyclic AMP-Dependent Protein Kinases / metabolism*
  • Disease Models, Animal
  • Humans
  • Macaca mulatta*
  • Male
  • Neurons / metabolism
  • Phosphorylation
  • Prefrontal Cortex / pathology
  • Rats
  • Ryanodine Receptor Calcium Release Channel
  • tau Proteins / metabolism*


  • Ryanodine Receptor Calcium Release Channel
  • tau Proteins
  • Cyclic AMP-Dependent Protein Kinases
  • Calcium