REDD1 Is Involved in Amyloid beta-Induced Synaptic Dysfunction and Memory Impairment
- Authors
- Yi, J.H.; Kwon, H.; Cho, E.; Jeon, J.; Lee, J.; Lee, Y.C.; Cho, J.H.; Jun, M.; Moon, M.; Ryu, J.H.; Kim, J.-S.; Choi, J.W.; Park, S.J.; Lee, S.; Kim, D.H.
- Issue Date
- Dec-2020
- Publisher
- MDPI
- Keywords
- Alzheimer’s disease; Aβ; Hippocampal long-term potentiation; Learning and memory; REDD1
- Citation
- International Journal of Molecular Sciences, v.21, no.24, pp.1 - 13
- Journal Title
- International Journal of Molecular Sciences
- Volume
- 21
- Number
- 24
- Start Page
- 1
- End Page
- 13
- URI
- https://scholarworks.bwise.kr/gachon/handle/2020.sw.gachon/79750
- DOI
- 10.3390/ijms21249482
- ISSN
- 1661-6596
- Abstract
- Alzheimer’s disease (AD) is a neurodegenerative disease characterized by neurological dysfunction, including memory impairment, attributed to the accumulation of amyloid β (Aβ) in the brain. Although several studies reported possible mechanisms involved in Aβ pathology, much remains unknown. Previous findings suggested that a protein regulated in development and DNA damage response 1 (REDD1), a stress-coping regulator, is an Aβ-responsive gene involved in Aβ cytotoxicity. However, we still do not know how Aβ increases the level of REDD1 and whether REDD1 mediates Aβ-induced synaptic dysfunction. To elucidate this, we examined the effect of Aβ on REDD1-expression using acute hippocampal slices from mice, and the effect of REDD1 short hairpin RNA (shRNA) on Aβ-induced synaptic dysfunction. Lastly, we observed the effect of REDD1 shRNA on memory deficit in an AD-like mouse model. Through the experiments, we found that Aβ-incubated acute hippocampal slices showed increased REDD1 levels. Moreover, Aβ injection into the lateral ventricle increased REDD1 levels in the hippocampus. Anisomycin, but not actinomycin D, blocked Aβ-induced increase in REDD1 levels in the acute hippocampal slices, suggesting that Aβ may increase REDD1 translation rather than transcription. Aβ activated Fyn/ERK/S6 cascade, and inhibitors for Fyn/ERK/S6 or mGluR5 blocked Aβ-induced REDD1 upregulation. REDD1 inducer, a transcriptional activator, and Aβ blocked synaptic plasticity in the acute hippocampal slices. REDD1 inducer inhibited mTOR/Akt signaling. REDD1 shRNA blocked Aβ-induced synaptic deficits. REDD1 shRNA also blocked Aβ-induced memory deficits in passive-avoidance and object-recognition tests. Collectively, these results demonstrate that REDD1 participates in Aβ pathology and could be a target for AD therapy. © 2020 by the authors. Licensee MDPI, Basel, Switzerland.
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