TY  - JOUR
AU  - Pérez-Sisqués, Leticia
AU  - Sancho-Balsells, Anna
AU  - Solana-Balaguer, Júlia
AU  - Campoy-Campos, Genís
AU  - Vives-Isern, Marcel
AU  - Soler-Palazón, Ferran
AU  - Anglada-Huguet, Marta
AU  - López-Toledano, Miguel-Ángel
AU  - Mandelkow, Eva-Maria
AU  - Alberch, Jordi
AU  - Giralt, Albert
AU  - Malagelada, Cristina
TI  - RTP801/REDD1 contributes to neuroinflammation severity and memory impairments in Alzheimer’s disease
JO  - Cell death & disease
VL  - 12
IS  - 6
SN  - 2041-4889
CY  - London [u.a.]
PB  - Nature Publishing Group
M1  - DZNE-2021-00368
SP  - 616
PY  - 2021
AB  - 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. 
KW  - Alzheimer Disease: complications
KW  - Alzheimer Disease: genetics
KW  - Alzheimer Disease: pathology
KW  - Animals
KW  - Case-Control Studies
KW  - Disease Models, Animal
KW  - Encephalitis: etiology
KW  - Encephalitis: genetics
KW  - Encephalitis: pathology
KW  - Female
KW  - Humans
KW  - Male
KW  - Memory Disorders: etiology
KW  - Memory Disorders: genetics
KW  - Memory Disorders: pathology
KW  - Mice
KW  - Mice, Transgenic
KW  - Neuroimmunomodulation: genetics
KW  - Neurotoxicity Syndromes: etiology
KW  - Neurotoxicity Syndromes: genetics
KW  - Neurotoxicity Syndromes: pathology
KW  - Severity of Illness Index
KW  - Transcription Factors: physiology
LB  - PUB:(DE-HGF)16
C6  - pmid:34131105
C6  - 34131105
C2  - pmc:PMC8206344
DO  - DOI:10.1038/s41419-021-03899-y
UR  - https://pub.dzne.de/record/154788
ER  -