RTP801/REDD1 contributes to neuroinflammation severity and memory impairments in Alzheimer’s disease

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.

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].…”

“…No significant correlation was found between RTP801 levels and Vonsattel stages (Figure 1c). GFAP (a marker of astrocytes) and Iba1 (a marker of microglia) levels were increased in HD patients (Figure 1d & f) and positively correlated with RTP801 levels (Figure 1 e & g), further suggesting that RTP801 levels could be a marker of gliosis in HD [36].…”

“…For mice undergoing surgeries, the dorsal and ventral hippocampus from the left hemisphere were dissected out separately. Crude synaptosomal fractions were obtained as described elsewhere [36]. Protein concentration of all samples was established with Bradford reagent (Biorad) following the manufacturer's instructions.…”

“…Moreover, RTP801 abrogation increases GluA1 and TrkB levels [32]. RTP801 protein levels are also elevated in Parkinson's disease (PD) [33,34], major depression [35] and Alzheimer's disease (AD) [36]. Interestingly, RTP801 gene, DDIT4, is one of the top three common upregulated transcripts in postmortem brains from HD and PD patients [37].…”

“…In addition, we recently described that RTP801 is a crucial contributor to neuroinflammation and memory impairments in AD since its downregulation in hippocampal neurons prevents cognitive deficits in the 5xFAD mouse model and reduces inflammatory markers [36].…”