Exploring How Low Oxygen Post Conditioning Improves Stroke-Induced Cognitive Impairment: A Consideration of Amyloid-Beta Loading and Other Mechanisms.

Zidan Zhao,Clifford Tebay,Kirby E Warren,Rebecca J Hood,Ole P Ottersen,Marina Ilicic,Sarah J Johnson,Sonia Sanchez Bezanilla,Murielle G Kluge,Frederick R Walker,Lin Kooi Ong,Giovanni Pietrogrande,Michael Nilsson

doi:10.3389/fneur.2021.585189

Abstract

Cognitive impairment is a common and disruptive outcome for stroke survivors, which is recognized to be notoriously difficult to treat. Previously, we have shown that low oxygen post-conditioning (LOPC) improves motor function and limits secondary neuronal loss in the thalamus after experimental stroke. There is also emerging evidence that LOPC may improve cognitive function post-stroke. In the current study we aimed to explore how exposure to LOPC may improve cognition post-stroke. Experimental stroke was induced using photothrombotic occlusion in adult, male C57BL/6 mice. At 72 h post-stroke animals were randomly assigned to either normal atmospheric air or to one of two low oxygen (11% O2) exposure groups (either 8 or 24 h/day for 14 days). Cognition was assessed during the treatment phase using a touchscreen based paired-associate learning assessment. At the end of treatment (17 days post-stroke) mice were euthanized and tissue was collected for subsequent histology and biochemical analysis. LOPC (both 8 and 24 h) enhanced learning and memory in the 2nd week post-stroke when compared with stroke animals exposed to atmospheric air. Additionally we observed LOPC was associated with lower levels of neuronal loss, the restoration of several vascular deficits, as well as a reduction in the severity of the amyloid-beta (Aβ) burden. These findings provide further insight into the pro-cognitive benefits of LOPC.

Highlights

Cognitive impairment has been reported as one of the most debilitating side-effects of stroke, impacting up to 80% of survivors [1, 2]
We have recently identified a number of mechanisms that correlate with post-stroke cognitive impairment including loss of neural tissue and vasculature, the accumulation of neurotoxic proteins including amyloid-beta (Aβ) [20], vascular leakage and aquaporin four (AQP4) depolarization [20]
We have considered the impact of low oxygen post-conditioning (LOPC) on several genes involved in regulating the expression of Aβ including production of Aβ [amyloid precursor protein (APP) [21]; beta secretase enzyme−1 (BACE) [22]; tumor necrosis factor α (TNFα) converting enzyme (TACE) [23]], transport of Aβ across the blood-brain barrier into the parenchyma [receptor for advanced glycation end products (RAGE) [24]], Aβ degrading enzymes [neprilysin (NEP) [25], endothelin-converting enzyme (ECE) [26] and insulin-degrading enzyme (IDE) [25]] and clearance of Aβ [low-density lipoprotein receptor-related protein 1 (LRP1) [27,28,29]]

Summary

Introduction

Cognitive impairment has been reported as one of the most debilitating side-effects of stroke, impacting up to 80% of survivors [1, 2]. Problems with memory, learning, and attention can significantly impact a survivor’s functional independence and several studies have reported that increased levels of cognitive impairment are associated with lower levels of self-reported quality of life [3] This situation has triggered a substantial effort both clinically and pre-clinically to develop effective strategies to improve cognitive function post-stroke [4, 5]. Recent evidence has shown pro-cognitive effects of exogenously delivered growth hormone post-stroke [6,7,8,9] Another promising procognitive therapy has been the use of intermittent exposure to a reduced oxygen environment [10, 11]. This non-pharmacological approach has numerous advantages over current strategies including its well-characterized and acceptable safety-profile, relatively low cost, ease of delivery and scalability

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Conclusion