Explore the Comparative Biology on Effects of Skin Ulceration on AD-Pathological Neurodegeneration

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ABSTRACT This application is in response to “PAR-17-039 Comparative Biology of Neurodegeneration”. Many aged Americans who suffer from Alzheimer’s disease (AD) also suffer from chronic skin ulcers. However, the effects of chronic skin ulceration on AD pathogenesis are poorly understood, leaving a gap in our knowledge. Inflammation-resolving (pro-resolving) lipid mediators [resolvin D1 (RvD1) and resolvin D5 (RvD5)] are present in healthy human and mouse brains. RvD1 and RvD5 are endogenous and produced by endogenous enzymes from ω-3 DHA. RvD1 or RvD5 switches macrophages (Ms) of AD patients to an M2 anti-inflammatory reparative phenotype and reverses the Aβ-induced M expression of inflammatory cytokines. Our pilot data suggest that the chronic pressure ulceration (PU) induced reduction of RvDs (the inflammation-resolving capacity) increases brain neuroinflammation and explains the PU promotion of AD-pathological neurodegeneration in 5xFAD mice. We hypothesize that chronic PU increases AD-pathological neurodegeneration and that this increase occurs at least partly via induction of chronic inflammation and reduction of inflammation-resolving capacity, manifested as the reduced levels of pro-resolving lipid mediators, including RvD1 and RvD5, both systemically and in brains. We will test our hypothesis via comparative biological approaches using both mouse and rat models of AD. Aim 1. We will induce chronic pressure ulceration (PU) in the skin of 5xFAD mice and TgF344-AD rats by pressure (ischemia/reperfusion) and compare results from these mice and rats in the following studies: 1A) Determine chronic PU effects on brain A- and/or tau-pathology-associated neurodegeneration and behavior readout (cognitive dysfunction) as well as potential age-dependence for these effects. 1B) Determine the reduction of inflammation-resolving capability in brains and systemic circulation as chronic PU effects on AD-pathological neurodegeneration. We will measure the pro-resolving capacity represented by targeted pro-resolving lipidomes (resolvin D-series) and inflammation status represented by targeted pro-inflammatory lipidome and cytokines. 1C) Decipher the chronic PU-induced activation of microglia and astrocytes and infiltration of blood leukocytes in brains in AD neurodegeneration. 1D) Modulate the inflammation-resolving capacity and inflammation by intranasal treatment of 5xFAD mice and TgF344-AD rats with RvD1 or RvD5 and compare the outcome to the results of 1A to 1C. Overall impact: This study will provide initial phase mechanistic knowledge that chronic PU exacerbates AD-neurodegeneration by reducing inflammation-resolving capability in circulation system and brains. It will determine how the responses of different animal species to chronic PU in the inflammation resolution of brains and systematic circulation affect AD neurodegeneration and onset. This R21 has considerable risk but will identify an innovative concept, mechanism, and intervention target to prevent and mitigate the risk imposed by chronic skin ulceration on AD-pathological neurodegeneration in the elderly.