RESUMEN
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 Aß 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.
Asunto(s)
Enfermedad de Alzheimer/genética , Encefalitis/genética , Trastornos de la Memoria/genética , Factores de Transcripción/fisiología , Enfermedad de Alzheimer/complicaciones , Enfermedad de Alzheimer/patología , Animales , Estudios de Casos y Controles , Modelos Animales de Enfermedad , Encefalitis/etiología , Encefalitis/patología , Femenino , Humanos , Masculino , Trastornos de la Memoria/etiología , Trastornos de la Memoria/patología , Ratones , Ratones Transgénicos , Neuroinmunomodulación/genética , Síndromes de Neurotoxicidad/etiología , Síndromes de Neurotoxicidad/genética , Síndromes de Neurotoxicidad/patología , Índice de Severidad de la EnfermedadRESUMEN
RTP801/REDD1 is a stress-regulated protein whose levels are increased in several neurodegenerative diseases such as Parkinson's, Alzheimer's, and Huntington's diseases (HD). RTP801 downregulation ameliorates behavioral abnormalities in several mouse models of these disorders. In HD, RTP801 mediates mutant huntingtin (mhtt) toxicity in in vitro models and its levels are increased in human iPSCs, human postmortem putamen samples, and in striatal synaptosomes from mouse models of the disease. Here, we investigated the role of RTP801 in the hippocampal pathophysiology of HD. We found that RTP801 levels are increased in the hippocampus of HD patients in correlation with gliosis markers. Although RTP801 expression is not altered in the hippocampus of the R6/1 mouse model of HD, neuronal RTP801 silencing in the dorsal hippocampus with shRNA containing AAV particles ameliorates cognitive alterations. This recovery is associated with a partial rescue of synaptic markers and with a reduction in inflammatory events, especially microgliosis. Altogether, our results indicate that RTP801 could be a marker of hippocampal neuroinflammation in HD patients and a promising therapeutic target of the disease.
