Abstract
RTP801/REDD1 is a stress-regulated protein whose upregulation is necessary and sufficient to trigger neuronal death. Its downregulation in Parkinson’s and Huntington’s disease models ameliorates the pathological phenotypes. In the context of Alzheimer’s disease (AD), the coding gene for RTP801, DDIT4, is responsive to Aβ and modulates its cytotoxicity in vitro. Also, RTP801 mRNA levels are increased in AD patients’ lymphocytes. However, the involvement of RTP801 in the pathophysiology of AD has not been yet tested. Here, we demonstrate that RTP801 levels are increased in postmortem hippocampal samples from AD patients. Interestingly, RTP801 protein levels correlated with both Braak and Thal stages of the disease and with GFAP expression. RTP801 levels are also upregulated in hippocampal synaptosomal fractions obtained from murine 5xFAD and rTg4510 mice models of the disease. A local RTP801 knockdown in the 5xFAD hippocampal neurons with shRNA-containing AAV particles ameliorates cognitive deficits in 7-month-old animals. Upon RTP801 silencing in the 5xFAD mice, no major changes were detected in hippocampal synaptic markers or spine density. Importantly, we found an unanticipated recovery of several gliosis hallmarks and inflammasome key proteins upon neuronal RTP801 downregulation in the 5xFAD mice. Altogether our results suggest that RTP801 could be a potential future target for theranostic studies since it could be a biomarker of neuroinflammation and neurotoxicity severity of the disease and, at the same time, a promising therapeutic target in the treatment of AD.
Highlights
Alzheimer’s disease (AD), the most common type of dementia affecting millions of people worldwide, is characterized by progressive cognitive impairment, typically beginning with memory deterioration and followed by executive dysfunction and language, visual and practical problems along with emotional and psychiatric symptoms [1, 2]
We found that the WT shCt, WT shRTP801, and 5xFAD shRTP801 mice explored significantly longer the novel arm than the familiar one whereas 5xFAD shCt mice showed no preference compared to controls (Fig. 1A, B)
RTP801 levels in human postmortem hippocampal samples correlated with Braak and Thal stages that classify disease progression and severity
Summary
Alzheimer’s disease (AD), the most common type of dementia affecting millions of people worldwide, is characterized by progressive cognitive impairment, typically beginning with memory deterioration and followed by executive dysfunction and language, visual and practical problems along with emotional and psychiatric symptoms [1, 2]. We investigated whether RTP801 is involved in AD dorsal hippocampus of the 5xFAD mice could improve their pathogenesis using human postmortem AD samples and trans- memory deficits. To test this hypothesis, 6-month-old WT and genic animal models of the disease. Our results suggest a putative role of [34, 35] In this test, the increased time spent in the open arms RTP801 in the inflammatory response associated with AD and showed by 5xFAD shCt mice compared with WT shCt mice was not frame RTP801 as a novel target in AD. In the passive avoidance test, the 5xFAD shCt mice showed significantly lower latencies to step-through in the testing session compared
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