Administrative Supplement: Postoperative Delirium and Alzheimer's Disease Related Dementias

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Postoperative delirium (POD) is the most common postoperative complication among older patients and is associated with substantially increased rates of morbidity and mortality, increased cost of care, and risk of developing Alzheimer’s disease (AD) and AD related dementias (AD/ADRD). However, the pathogenesis of POD is still largely unknown, and this gap in knowledge impedes current efforts in preventing and treating POD. To further study the POD pathogenesis, we have established a nanoneedle technology to measure blood concentrations of Tau phosphorylation at threonine 217 (Tau-pT217) and threonine 181 (Tau-pT181). Consistent with the notion that Tau-pT217 and Tau-pT181 are the newly identified biomarker of early stage of AD, our preliminary studies showed that open abdominal surgery under isoflurane anesthesia (anesthesia/surgery) increased Tau-pT217 and Tau-pT181 amounts in blood, lungs and brain, accompanied by decreases in B cells in blood of aged mice. Thus, the proposed research will extend these studies to establish trafficking of Tau-pT217 and Tau-pT181 from blood to brain as the pathogenesis of POD by testing the following hypothesis: anesthesia/surgery enhances Tau-pT217 and Tau-pT181 generation and promotes Tau-pT217 and Tau-pT181 trafficking from blood to brain, leading to delirium-like behavior in mice. We will employ biochemical and genetic tools through in vivo (mice) approach to accomplish three Specific Aims: 1) We will evaluate the effects of anesthesia/surgery on the amounts of Tau-pT217 and Tau-pT181 in blood, lungs and brain of adult (3 months-old) and aged (18 months-old) wild-type mice, and adult (3 months-old) AD transgenic mice. 2) We will perform studies to determine the trafficking of Tau-pT217 and Tau-pT181 from blood to brain in wild-type mice and Tau knockout mice by using conditioned blood, synthesized Tau-pT217 and Tau-pT181 peptides or parabiosis in mice. 3) We will assess whether treatment with WS635 or Vitamin K2 (protector of mitochondrial function), or B cells can mitigate the anesthesia/surgery-induced increases in Tau- pT217 and Tau-pT181 amounts, and delirium-like behaviors in aged wild-type mice and AD transgenic mice. We will include adult wild-type (3 months-old) mice versus age matched (3 months-old) AD transgenic and aged wild-type (18 months-old) mice (with higher pTau levels), and employ a label-free nano-biosensing system for biomolecular analysis (nanoneedle technology). This proposal aims to investigate an understudied topic in innovative systems through testing novel hypotheses. Our efforts could ultimately help to develop prevention and treatment methods towards POD, leading to safer surgical care and better post-operative outcomes for senior and AD/ADRD patients, leading to the development of strategies to prevent AD/ADRD.