Journal
ALZHEIMERS & DEMENTIA
Volume 17, Issue 6, Pages 920-932Publisher
WILEY
DOI: 10.1002/alz.12325
Keywords
aging; association cortex; calpain; impaired cognition; macaque; pyramidal cells; PKA; ryanodine receptor; tau
Categories
Funding
- NIMH [R01MH113257]
- National Institutes of Health (NIH) [DP1AG047744-01, R01AG061190-02]
- Alzheimer's Association Research Fellowship [AARF-17-533294]
- NIH [AG047270, AG062306, AG066508, T32 NS41228]
- State of Connecticut Department ofMental Health and Addiction Services
- Gruber Fellowship
- Alzheimer's Disease Research Unit
- American Federation for Aging Research/Diamond Postdoctoral Fellowship
- [F31AG063425]
- [DA023999]
- [AG052986]
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Aged monkeys naturally develop hyperphosphorylated tau, including AD biomarkers and early tau pathology markers, which correlates with evidence of increased calcium leak. In vitro, calcium also regulates early tau phosphorylation. Blocking RyRs with S107 improves neuronal firing and cognitive performance in aged macaques, suggesting dysregulated calcium signaling can be a potential therapeutic target.
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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