Pathogenesis of Postoperative Cognitive Dysfunction
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Perioperative neurocognitive disorder (PND), the most common postoperative complication among geriatric patients and an important research area in the field of Anesthesia, Surgery and Geriatrics, is potentially associated with increased risk of Alzheimer’s disease (AD) and AD-related dementias (ADRD) , morbidity, mortality, and cost of care. However, the pathogenesis of PND is still largely unknown, which impede the further studies into PND. Consistent with the notion that phosphorylated Tau (pTau) and mitochondria permeability transition pore component Cyclophilin D (CypD) regulate cognitive function, our published work and preliminary studies in mice showed that blood monocytes are the potential peripheral factor of PND pathogenesis and interactions between Tau phosphorylated at threonine 217 (Tau-PT217) and CypD in monocytes activate NF-κB, inducing inflammation and neuroinflammation. In addition, CypD levels are higher in blood monocytes of AD transgenic and aged mice. Thus, the proposed research will further identify the role of blood monocytes on PND pathogenesis by assessing the effects of anesthesia/surgery on pTau and CypD levels in blood monocytes, inflammation, neuroinflammation, brain function, and cognition in mice. We will define a multifactorial model of PND pathogenesis where the interaction between increased pTau (caused by anesthesia/surgery, the precipitating factor and insulting action) and elevated CypD (associated with aging- or AD gene mutation, the predisposing factor and gating regulation) in blood monocytes is necessary to generate PND. The hypothesis of the proposed study is that anesthesia/surgery-induced increases in pTau interact with aging- and AD gene mutation-associated elevations of CypD in blood monocytes, leading to inflammation, neuroinflammation, brain dysfunction, and PND-like behavior in mice. We will employ both genetic and pharmacological tools through molecular, cellular and behavioral approaches to accomplish three Specific Aims: (1) we will assess the effects of anesthesia/surgery on Tau, pTau, CypD, and cytokines in monocytes, blood, and brain of mice, brain function, and cognitive functions of mice; (2) we will use Tau and CypD knockout chimeric mice to further investigate the interaction between pTau and CypD as potential mechanism underlying PND pathogenesis at the single molecular level, in monocytes, blood, brain, and behavior of mice; and (3) we will assess whether inhibiting the pTau-CypD-NF-κB-NLRP3 inflammasome cascade can reduce PND and its pathogenesis. Notably, we will use wild-type and adult (4-month-old) mice versus age matched AD transgenic and aged (18-month-old) mice while employing nanotechnology, electrophysiology, in vivo cell depletion, real time in vivo two-photon, Western blot, immunohistochemistry, behavioral tests and others. This proposal aims to investigate an understudied topic in innovative systems by testing novel hypotheses, which would develop effective strategies to reduce PND for AD and geriatric patients and to improve postoperative outcomes in these patients, ultimately informing prevention and treatment strategies for ADRD.
