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

Abstract

Introduction:The etiology of sporadic Alzheimer's disease (AD) requires nongenetically 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.

The Rhesus Macaque as a Translational Model for Neurodegeneration and Alzheimer’s Disease

“…While the lack of neuron loss in all other analyzed areas seems to indicate that rhesus macaques do not naturally lose neurons as they age, it is interesting to note that the multiple cohorts of rhesus monkeys have shown p-tau tangles in the hippocampus (i.e., Paspalas et al, 2018;Datta et al, 2021). Furthermore, in clinical studies it has been shown that p-tau tangles are associated with cell death-one of the primary drivers of cognitive decline in AD (Peters et al, 1994;Datta et al, 2021). Taken together, the overall consensus is that rhesus macaques do not show the distinctive neuronal loss that characterizes the later stages of AD in humans, and which is associated with dementia.…”

“…This brain region is highly sensitive to cognitive and pathological aging changes, critical to memory consolidation, and undergoes significant shrinkage in AD (Freeman et al, 2008;Squire et al, 2015). While the lack of neuron loss in all other analyzed areas seems to indicate that rhesus macaques do not naturally lose neurons as they age, it is interesting to note that the multiple cohorts of rhesus monkeys have shown p-tau tangles in the hippocampus (i.e., Paspalas et al, 2018;Datta et al, 2021). Furthermore, in clinical studies it has been shown that p-tau tangles are associated with cell death-one of the primary drivers of cognitive decline in AD (Peters et al, 1994;Datta et al, 2021).…”

“…However, in 2018 Paspalas et al reported detection of p-tau in the rhesus macaque entorhinal cortex, which has led to a resurgence in interest surrounding non-human primate p-tau. In addition to this initial landmark study, laboratories are currently researching both natural p-tau accumulation and tauopathy induction models in the rhesus macaque (i.e., Beckman et al, 2021;Datta et al, 2021). There is still much work to be done characterizing natural tauopathy in the rhesus macaque, but it has generally been observed that most monkeys do not live long enough to develop pathological tauopathy.…”

“…There is still much work to be done characterizing natural tauopathy in the rhesus macaque, but it has generally been observed that most monkeys do not live long enough to develop pathological tauopathy. For instance, most overt tauopathy appears to occur mainly in macaques over the age of 30 years, and very few primate facilities have a cohort of these very old animals (Paspalas et al, 2018;Datta et al, 2021). Therefore, non-human primate induction models become highly relevant: if the same natural pathways that lead to tauopathy can be dysregulated or stimulated earlier in life, researchers can study the etiology and progression of the proteinopathy across many years, and monkeys would likely achieve more advanced states of tauopathy.…”

“…This could mimic neurodegeneration or advanced stages of human brain aging, which can inform clinical progression of the disease; if researchers can induce tauopathy into a further progressed state in the macaque, the inverse processes are logical targets for early AD intervention. It should be emphasized that relatively few rhesus monkeys live beyond ∼25 years, which is prior to the age at which they begin to show significant hippocampal tauopathy (Paspalas et al, 2018;Datta et al, 2021); thus, the systematic study of p-tau induction will be critically important in further developing the macaque AD model.…”