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Age-related calcium dysregulation linked with tau pathology and impaired cognition in non-human primates.
Datta, Dibyadeep; Leslie, Shannon N; Wang, Min; Morozov, Yury M; Yang, Shengtao; Mentone, SueAnn; Zeiss, Caroline; Duque, Alvaro; Rakic, Pasko; Horvath, Tamas L; van Dyck, Christopher H; Nairn, Angus C; Arnsten, Amy F T.
Afiliação
  • Datta D; Departments of Neuroscience, School of Medicine, Yale University, Connecticut, USA.
  • Leslie SN; Department of Psychiatry, School of Medicine, Yale University, Connecticut, USA.
  • Wang M; Interdepartmental Neuroscience Program, School of Medicine, Yale University, Connecticut, USA.
  • Morozov YM; Departments of Neuroscience, School of Medicine, Yale University, Connecticut, USA.
  • Yang S; Departments of Neuroscience, School of Medicine, Yale University, Connecticut, USA.
  • Mentone S; Departments of Neuroscience, School of Medicine, Yale University, Connecticut, USA.
  • Zeiss C; Departments of Neuroscience, School of Medicine, Yale University, Connecticut, USA.
  • Duque A; Department of Comparative Medicine, School of Medicine, Yale University, Connecticut, USA.
  • Rakic P; Departments of Neuroscience, School of Medicine, Yale University, Connecticut, USA.
  • Horvath TL; Departments of Neuroscience, School of Medicine, Yale University, Connecticut, USA.
  • van Dyck CH; Department of Comparative Medicine, School of Medicine, Yale University, Connecticut, USA.
  • Nairn AC; Departments of Neuroscience, School of Medicine, Yale University, Connecticut, USA.
  • Arnsten AFT; Department of Psychiatry, School of Medicine, Yale University, Connecticut, USA.
Alzheimers Dement ; 17(6): 920-932, 2021 06.
Article em En | MEDLINE | ID: mdl-33829643
ABSTRACT

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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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Cálcio / Proteínas tau / Proteínas Quinases Dependentes de AMP Cíclico / Disfunção Cognitiva / Macaca mulatta Tipo de estudo: Prognostic_studies Limite: Animals / Humans / Male Idioma: En Revista: Alzheimers Dement Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Estados Unidos
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Cálcio / Proteínas tau / Proteínas Quinases Dependentes de AMP Cíclico / Disfunção Cognitiva / Macaca mulatta Tipo de estudo: Prognostic_studies Limite: Animals / Humans / Male Idioma: En Revista: Alzheimers Dement Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Estados Unidos