The glymphatic system and perioperative neurocognitive disorder
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Project Summary/Abstract Perioperative neurocognitive disorder (PND) is the most common postoperative complication in older adults and represents a growing challenge in anesthesiology, surgery, and geriatric medicine. PND is associated with increased risk for Alzheimer’s disease (AD) and related dementias (ADRD), as well as higher morbidity, mortality, and healthcare costs. Despite its prevalence and clinical significance, the underlying pathophysiology of PND remains poorly understood, limiting the development of effective targeted therapies. Emerging evidence, including our own, implicates impaired clearance of neurotoxic proteins such as β-amyloid (Aβ) and phosphorylated tau (p-tau), in PND pathogenesis. The glymphatic system, a brain-wide perivascular clearance pathway, facilitates cerebrospinal fluid (CSF)-interstitial fluid (ISF) exchange and promotes the removal of Aβ and p-tau. Glymphatic function depends on the polarized localization of aquaporin-4 (AQP4) water channels to astrocytic endfeet surrounding cerebral vasculature. Both aging and AD are associated with diminished glymphatic flow and AQP4 mislocalization. Our recent work and preliminary data show that anesthesia/surgery can further impair glymphatic function and disrupt AQP4 polarization, particularly in aged and AD-vulnerable brains. We also find that anesthesia/surgery robustly activates the endoplasmic reticulum (ER) stress sensor PERK in astrocytes and upregulates casein kinase 2 (CK2), a kinase involved in AQP4 trafficking. These findings support our central hypothesis that anesthesia/surgery exacerbates glymphatic dysfunction in aging and AD- vulnerable brains via PERK/CK2-mediated AQP4 mislocalization, leading to impaired clearance of neurotoxic proteins, neuronal dysfunction, and PND-like cognitive decline. To test this hypothesis, we propose the following specific aims. Aim 1: Characterize the effects of anesthesia/surgery on glymphatic function, neurotoxic protein accumulation, and cognitive outcomes in adult (3-month), aged (18-month) wild-type mice, and presymptomatic AD transgenic (5xFAD; 3-month) mice. Aim 2: Determine whether astrocytic PERK activation mediates anesthesia/surgery-induced AQP4 mislocalization and glymphatic dysfunction using inducible astrocyte-specific PERK knockout mice and pharmacologic PERK inhibition. Aim 3: Test whether CK2 acts downstream of PERK to promote AQP4 mislocalization, glymphatic impairment, and postoperative cognitive vulnerability. This project integrates advanced and innovative approaches, including in vivo two-photon imaging of CSF tracer dynamics, nanoneedle-based ultrasensitive biomarker detection, RNAscope in situ hybridization, astrocyte-specific genetic manipulation, and validated behavioral assays. By elucidating molecular and cellular mechanisms linking surgical stress to glymphatic failure and neurocognitive decline, this research addresses a critical gap in our understanding of PND pathogenesis. Findings from this work may uncover novel therapeutic targets to preserve glymphatic function, prevent or treat PND, and reduce long-term ADRD risk in vulnerable surgical populations.
