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Age‐related calcium dysregulation linked with tau pathology and impaired cognition in non‐human primates
Author(s) -
Datta Dibyadeep,
Leslie Shan N.,
Wang Min,
Morozov Yury M.,
Yang Shengtao,
Mentone SueAnn,
Zeiss Caroline,
Duque Alvaro,
Rakic Pasko,
Horvath Tamas L.,
Dyck Christopher H.,
Nairn Angus C.,
Arnsten Amy F.T.
Publication year - 2021
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.12325
Subject(s) - calbindin , neuroscience , ryanodine receptor , calcium , macaque , cyclic adenosine monophosphate , calcium signaling , medicine , biology , endocrinology , chemistry , receptor
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.