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

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.

RTP801/REDD1 Is Involved in Neuroinflammation and Modulates Cognitive Dysfunction in Huntington’s Disease

“…For instance, in WT animals, RTP801 overexpression impairs contextual-fear memory consolidation, while RTP801 hippocampal silencing enhances this process [ 52 ]. In line with this, RTP801 hippocampal downregulation prevents memory impairments and reduces neuroinflammation in the 5xFAD mouse model of AD [ 35 ] and diminishes amyloid-beta-induced synaptic dysfunction [ 53 ].…”

RTP801/REDD1 is Involved in Neuroinflammation and Modulates Cognitive Dysfunction in Huntington’s Disease

“…For instance, in WT animals, RTP801 overexpression impairs contextual-fear memory consolidation, while RTP801 hippocampal silencing enhances this process [52]. In line with this, RTP801 hippocampal downregulation prevents memory impairments and reduces neuroinflammation in the 5xFAD mouse model of AD [36] and diminishes amyloid-beta induced synaptic dysfunction [53].…”

Immunomagnetic sequential ultrafiltration (iSUF) platform for enrichment and purification of extracellular vesicles from biofluids

“…However, iSUF shows better recovery for sEVs and m/l-EVs. The wide upper range showed by UC could be indicative that we measure aggregates of EVs 103 – 106 . Our measurements are in agreement with MISEV 2018 since sEVs, and m/l-EVs are in the 100–150 nm and larger than 200 nm, respectively 36 , 63 , 107 – 111 .…”