REDD1 Is Involved in Amyloid β-Induced Synaptic Dysfunction and Memory Impairment.

Jee Hyun Yi,Se Jin Park,Young Choon Lee,Huiyoung Kwon,Minho Moon,Ji Woong Choi,Jong Hoon Ryu,Ji-Su Kim,Jeongwon Lee,Jong Hyun Cho,Dong Hyun Kim,Seungheon Lee,Eunbi Cho,Jieun Jeon,Mira Jun

doi:10.3390/ijms21249482

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.

Highlights

Alzheimer’s disease (AD) is the most common neurodegenerative disease associated with memory and cognitive impairment [1,2]
Intracerebroventricular injection of amyloid β (Aβ) (10 μM, 3 μL) into the hippocampal CA1 region increased REDD1 levels 24 h postinjection (t6 = 3.871, p < 0.05, n = 4/group; Figure 1B). These results suggest that Aβ may upregulate REDD1
REDD1 is required for Aβ-induced synaptic deficit and memory loss

Summary

Introduction

Alzheimer’s disease (AD) is the most common neurodegenerative disease associated with memory and cognitive impairment [1,2]. A stress-inducible protein is “regulated in development and DNA damage response 1” (REDD1), known as RTP801 or Dig, which is upregulated in response to a variety of cellular stresses such as nutrient and energy deprivation [6,7], hypoxia [8], DNA damage [9], and stress hormone glucocorticoids [10,11]. REDD1, a negative regulator of the mammalian target of rapamycin (mTOR), is involved in transcription and modulates Akt activity by suppressing mTOR via tuberous sclerosis complex 1 (TSC1)/tuberous sclerosis complex 2 (TSC2), and inactivation of Ra homolog enriched in brain (Rheb) [8]. Because mTOR is involved in diverse phenomena, such as autophagy [10], cell proliferation [6], and cell motility [12], its regulation by REDD1 has the potential to be a pharmacological target for various neurological diseases. A widely prescribed Type 2 diabetes drug, was found to induce mTOR inhibition and cell-cycle arrest through REDD1 [13]

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