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

Alzheimer's disease (AD) is a neurodegenerative disease characterized by neurological dysfunction, including memory impairment, attributed to the accumulation of amyloid beta (A beta) in the brain. Although several studies reported possible mechanisms involved in A beta 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 A beta-responsive gene involved in A beta cytotoxicity. However, we still do not know how A beta increases the level of REDD1 and whether REDD1 mediates A beta-induced synaptic dysfunction. To elucidate this, we examined the effect of A beta on REDD1-expression using acute hippocampal slices from mice, and the effect of REDD1 short hairpin RNA (shRNA) on A beta-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 A beta-incubated acute hippocampal slices showed increased REDD1 levels. Moreover, A beta injection into the lateral ventricle increased REDD1 levels in the hippocampus. Anisomycin, but not actinomycin D, blocked A beta-induced increase in REDD1 levels in the acute hippocampal slices, suggesting that A beta may increase REDD1 translation rather than transcription. A beta activated Fyn/ERK/S6 cascade, and inhibitors for Fyn/ERK/S6 or mGluR5 blocked A beta-induced REDD1 upregulation. REDD1 inducer, a transcriptional activator, and A beta blocked synaptic plasticity in the acute hippocampal slices. REDD1 inducer inhibited mTOR/Akt signaling. REDD1 shRNA blocked A beta-induced synaptic deficits. REDD1 shRNA also blocked A beta-induced memory deficits in passive-avoidance and object-recognition tests. Collectively, these results demonstrate that REDD1 participates in A beta pathology and could be a target for AD therapy.