Affiliations: [a] Department of Experimental and Applied Pharmacology, Centre of Excellence in Applied Biology, University of Pavia, Italy | [b] Department of Biomedical Sciences and Biotechnologies, University of Brescia, Italy | Section of Gerontology and Geriatrics, Department of Clinical and Experimental Medicine, University of Perugia, Italy
Correspondence:
[*]
Address for correspondence: Stefano Govoni, PhD, Department of Experimental and Applied Pharmacology, University of Pavia, Viale Taramelli 14, 27100 Pavia, Italy. E-mail: [email protected].
Note: [1] These authors contributed equally to this work.
Abstract: 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-β (Aβ) 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 Aβ. On this basis, we hypothesized that low amounts of soluble Aβ 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 Aβ 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.
Keywords: Alzheimer's disease, amyloid-β peptide, p53, protein tertiary structure, human peripheral cells, immunoprecipitation
