한빛사논문
- 조회517
Sara Cazzaro 1 2, Jung-A A Woo 1, Xinming Wang 1, Tian Liu 1, Shanon Rego 2, Teresa R Kee 1 2, Yeojung Koh 1 3 4, Edwin Vázquez-Rosa 3 4, Andrew A Pieper 3 4 5 6 7, David E Kang 1 8 *
1Department of Pathology, Case Western Reserve University, School of Medicine, Cleveland, OH 44106.
2Department of Molecular Medicine, University of South Florida Health College of Medicine, Tampa, FL 33620.
3Department of Psychiatry, Case Western Reserve University, School of Medicine, Cleveland, OH 44106.
4Institute for Transformative Molecular Medicine, Case Western Reserve University, School of Medicine, Cleveland, OH 44106.
5Department of Neuroscience, Case Western Reserve University, School of Medicine, Cleveland, OH 44106.
6Geriatric Psychiatry, Geriatric Research Education and Clinical Center, Louis Stokes Cleveland Veteran Affairs Medical Center, Cleveland, OH 44106.
7Brain Health Medicines, Center Harrington Discovery Institute, Cleveland, OH 44106.
8Louis Stokes Cleveland Veteran Affairs Medical Center, Cleveland, OH 44106.
*Corresponding author: correspondence to David E Kang
Abstract
Oxidative damage in the brain is one of the earliest drivers of pathology in Alzheimer’s disease (AD) and related dementias, both preceding and exacerbating clinical symptoms. In response to oxidative stress, nuclear factor erythroid 2-related factor 2 (Nrf2) is normally activated to protect the brain from oxidative damage. However, Nrf2-mediated defense against oxidative stress declines in AD, rendering the brain increasingly vulnerable to oxidative damage. Although this phenomenon has long been recognized, its mechanistic basis has been a mystery. Here, we demonstrate through in vitro and in vivo models, as well as human AD brain tissue, that Slingshot homolog-1 (SSH1) drives this effect by acting as a counterweight to neuroprotective Nrf2 in response to oxidative stress and disease. Specifically, oxidative stress-activated SSH1 suppresses nuclear Nrf2 signaling by sequestering Nrf2 complexes on actin filaments and augmenting Kelch-like ECH-associated protein 1 (Keap1)–Nrf2 interaction, independently of SSH1 phosphatase activity. We also show that Ssh1 elimination in AD models increases Nrf2 activation, which mitigates tau and amyloid-β accumulation and protects against oxidative injury, neuroinflammation, and neurodegeneration. Furthermore, loss of Ssh1 preserves normal synaptic function and transcriptomic patterns in tauP301S mice. Importantly, we also show that human AD brains exhibit highly elevated interactions of Nrf2 with both SSH1 and Keap1. Thus, we demonstrate here a unique mode of Nrf2 blockade that occurs through SSH1, which drives oxidative damage and ensuing pathogenesis in AD. Strategies to inhibit SSH1-mediated Nrf2 suppression while preserving normal SSH1 catalytic function may provide new neuroprotective therapies for AD and related dementias.
논문정보
- Research article
- 2023년 07월 (BRIC 등록일 2023-08-07)
- 국외 연구진
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