Unfolded p53: a potential biomarker for Alzheimer's disease.
The identification of biological markers of AD can improve diagnostic accuracy and therapy follow-up as well as provide information on the pathogenesis of the disease. We recently found that fibroblasts derived from AD patients expressed an altered conformational status of p53 and were less sensitive to p53-dependent apoptosis compared to fibroblasts from non-AD subjects. When investigating the mechanism of such alteration, we found that the exposure to nanomolar concentrations of amyloid-beta (Abeta) 1-40 peptide induced the expression of an unfolded p53 protein isoform in fibroblasts derived from non-AD subjects. These data suggest that the tertiary structure of p53 and the sensitivity to p53-dependent apoptosis is influenced by low concentrations of soluble Abeta. On this basis, we hypothesized that low amounts of soluble Abeta induce early pathological changes at cellular level that may precede the amyloidogenic cascade. One of these changes is the induction of a novel conformational state of p53. If low amounts of Abeta peptide, not resulting in cytotoxic effects, are responsible for p53 structure changes, it could be possible to consider the unfolded p53 both as an agent participating to the early pathogenesis and as a specific marker of the early stage of AD.
Lanni
Cristina
C
Department of Experimental and Applied Pharmacology, Centre of Excellence in Applied Biology, University of Pavia, Italy.
Uberti
Daniela
D
Racchi
Marco
M
Govoni
Stefano
S
Memo
Maurizio
M
D000368:Aged; D000544:Alzheimer Disease / Q000235:genetics*; D016229:Amyloid beta-Peptides / Q000235:genetics*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D016158:Genes, p53 / Q000235:genetics*; D006801:Humans; D008297:Male; D012867:Skin / Q000378:metabolism / Q000473:pathology
D016229:Amyloid beta-Peptides