| Abstrakt: |
Background: Calcium dysregulation may be an important etiological event in Alzheimer's Disease (AD). The presenilins (PS1/PS2) are components of the calcium‐storing smooth endoplasmic reticulum (SER), and PS1/PS2 mutations that cause autosomal dominant AD cause calcium leak from the SER. Recent studies of medial temporal lobe from animal models and patients with late‐onset AD have also found evidence of calcium leak from SER through PKA‐phosphorylated ryanodine receptors (pS2808RyR2). Thus, the SER may be a nexus for AD pathology. The current research used immunoelectron microscopy to visualize the SER in the aging rhesus monkey dorsolateral prefrontal cortex (dlPFC), a newly evolved brain region which subserves higher cognition and is vulnerable in AD. As aging increases calcium‐PKA signaling in dlPFC, we looked for evidence of pS2808RyR2, as well as PKA‐phosphorylated tau (pS214Tau), and for changes in the cAMP‐PKA regulatory protein, PDE4Ds. Finally, we examined the location of TREM2, a genetic risk factor for late‐onset AD that is linked to microglia, but was also observed on neuronal SER in the current study. Method: We used high‐spatial resolution immunoEM to localize PDE4D, pS2808RyR2, pS214Tau and TREM2 in aging rhesus monkey dlPFC. Result: The data show that the SER is a focus of age‐related pathology in association cortex, with loss of PDE4D from the SER in spines and dendrites, and increased PKA phosphorylation of pS2808RyR2, which causes calcium "leak". We also find evidence of increased PKA phosphorylation of pS214tau aggregating on the SER and microtubules, an important step that causes tau to detach from microtubules and aggregate, and primes tau for hyperphosphorylation and neurofibrillary tangle formation. Finally, we found TREM2 focused on the SER in spines and dendrites in neurons in addition to its expected location in glia. Thus, early‐onset (PS1/PS2), late‐onset (TREM2) and aging, all target the SER in the association cortical synapses most vulnerable to AD pathology. Conclusion: This nexus of genetic risks supports the hypothesis that calcium dysregulation is a key factor in AD neurodegeneration, an underappreciated mechanism in the AD field. Regulating internal calcium signaling in the aging cortex may provide an opportunity for therapeutic intervention at early stages of pathology. [ABSTRACT FROM AUTHOR] |
