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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.