PKR, a cognitive decline biomarker, can regulate translation via two consecutive molecular targets p53 and Redd1 in lymphocytes of AD patients.
In Alzheimer's disease (AD), the control of translation is dysregulated, precisely, two opposite pathways: double-stranded RNA-dependent protein kinase (PKR) is up-regulated and mammalian target of rapamycin (mTOR) is down-regulated. These biochemical alterations were found at the periphery in lymphocytes of AD patients and were significantly correlated with cognitive and memory test scores. However, the molecular crosslink between these two opposite signalling pathways remains unknown. The tumour suppressor p53 and Redd1 (regulated in development and DNA damage response) could be two downstream targets of active PKR to explain the breakdown of translation in AD patients. In this study, the protein and gene levels of p53 and Redd1 were assayed in lymphocytes of AD patients and in age-matched controls by Western blotting and RT-PCR. Furthermore, correlations were analysed with both the level of active PKR and the Mini Mental State Examination score (MMSE). The results show that the gene and protein levels of p53 and Redd1 were significantly increased about 1.5-fold for both gene and Redd1 protein and 2.3-fold for active p53 in AD lymphocytes compared to age-matched controls. Furthermore, statistical correlations between proteins and genes suggest that active PKR could phosphorylate p53 which could induce the transcription of Redd1 gene. No correlations were found between MMSE scores and levels of p53 or Redd1, contrary to active PKR levels. PKR represents a cognitive decline biomarker able to dysregulate translation via two consecutive targets p53 and Redd1 in AD lymphocytes.
Damjanac
Milena
M
Research Group on Brain Aging, University of Poitiers, France.
Page
Guylène
G
Research Group on Brain Aging, University of Poitiers, France.
Ragot
Stéphanie
S
Clinical Investigation Center, Poitiers University Hospital, France.
Laborie
Guillaume
G
Research Group on Brain Aging, University of Poitiers, France.
Gil
Roger
R
Research Group on Brain Aging, University of Poitiers, France.|Department of Neurology, Poitiers University Hospital, France.
Hugon
Jacques
J
Departments of Histology and Pathology, Lariboisière Hospital, University of Paris, France.
Paccalin
Marc
M
Research Group on Brain Aging, University of Poitiers, France.|Department of Geriatrics, Poitiers University Hospital, France.
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000097:blood*; D001483:Base Sequence; D015415:Biomarkers / Q000378:metabolism*; D015153:Blotting, Western; D003072:Cognition Disorders / Q000201:enzymology*; D017931:DNA Primers; D005260:Female; D006801:Humans; D008214:Lymphocytes / Q000378:metabolism*; D008297:Male; D014176:Protein Biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014157:Transcription Factors / Q000097:blood* / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000097:blood* / Q000235:genetics; D019892:eIF-2 Kinase / Q000378:metabolism*
D015415:Biomarkers; C469991:DDIT4 protein, human; D017931:DNA Primers; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D019892:eIF-2 Kinase