Does suppression of glymphatic flow explain why chronic neuropathic pain elevates the risk of developing Alzheimer-like dementia?

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The goal of this application for an administrative supplement for R01AT011439 is to expand ongoing studies of chronic neuropathic pain to include a murine model of Alzheimer’s disease (AD). It is known that more than 50% of patients with AD suffer from either acute or chronic pain. Pain in patients with AD is often unrecognized or undertreated, and current medical treatment can have considerable side-effects in dementia patients including adverse drug–drug interactions. Thus, an even greater need exists for identifying non-pharmacological approaches to reduce pain in patients suffering from Alzheimer disease than in the remaining population. Our underlying hypothesis is that the glymphatic system – a brain fluid transport system - sits at the crossroad of physiological and maladaptive responses to chronic neuropathic pain. We proposed that many of the classical presentations of chronic neuropathic pain are a consequence of glymphatic malfunction, including cytokine accumulation, neuronal hyperexcitability, and poor sleep quality. We are now proposing to expand the ongoing studies to include a murine model of Alzheimer disease: the APP/PSI mouse line. The proposed studies will test the hypothesis that pain induced by spared nerve injury (SNI) is more severe in the APP/PS1 mice than in age- matched controls because the glymphatic system is already suppressed. We will also test the corollary hypothesis that chronic neuropathic pain potently accelerates the loss of cognitive function and amyloid- aggregation due to the reduction of glymphatic clearance in APP/PS1 mice. We propose to systematically map the time course of chronic neuropathic pain in APP/PS1 mice and compare to age-matched controls in 4-, 8-, and 18-months old mice. We will test the following questions: Aim 1. Does suppression of glymphatic flow explain why chronic neuropathic pain elevates the risk of developing dementia? These experiments will correlate glymphatic clearance with both the severity of pain and severity of AD (cognitive test and amyloid- deposition) in 4-, 8-, and 18-month old mice APP/PS1 mice, age- matched littermate controls, and wildtype C57BL/6J mice. Aim 2. We propose that complementary interventions including omega-3 fatty acid supplementation, exercise, and improved sleep (induced by elevating temperature in the light phase) will lower baseline NE levels and improve both sleep architecture and glymphatic flow. The key endpoint of Aim 2 is to test whether the interventions preserve cognitive function in APP/PS1 mice and slow amyloid- aggregation. By collecting a large set of behavioral, physiological, and histological data in individual mice, including cytokine profile, sleep architecture, and norepinephrine levels, we will use correlation analyses will test the hypothesis that glymphatic clearance failure after SNI is the missing link explaining why neuropathic pain accelerates the progression of AD.