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Alzheimer's Research & Therapy
Published in: Alzheimer's Research & Therapy 1/2020

01-12-2020 | Alzheimer's Disease | Review

The pleiotropic role of p53 in functional/dysfunctional neurons: focus on pathogenesis and diagnosis of Alzheimer’s disease

Authors: Giulia Abate, Giovanni B. Frisoni, Jean-Christophe Bourdon, Simona Piccirella, Maurizio Memo, Daniela Uberti

Published in: Alzheimer's Research & Therapy | Issue 1/2020

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Abstract

Background

Understanding the earliest pathophysiological changes of Alzheimer’s disease (AD) may aid in the search for timely diagnostic biomarkers and effective disease-modifying therapies. The p53 protein is mostly known for its role in tumor suppression. However, emerging evidence supports that dysregulated p53 activity may contribute to various peripheral and brain alterations during the earliest stages of AD. This review describes the mechanisms through which p53 dysregulation may exacerbate AD pathology and how this could be used as a potential peripheral biomarker for early detection of the disease.

Main body

p53, known as the guardian of the genome, may underlie various compensation or defense mechanisms that prevent neurons from degeneration. These mechanisms include maintenance of redox homeostasis, regulation of inflammation, control of synaptic function, reduction of amyloid β peptides, and inhibition of neuronal cell cycle re-entry. Thereby, dysregulation of p53-dependent compensation mechanisms may contribute to neuronal dysfunction, thus leading to neurodegeneration. Interestingly, a conformational misfolded variant of p53, described in the literature as unfolded p53, which has lost its canonical structure and function, was observed in peripheral cells from mild cognitive impairment (MCI) and AD patients. In AD pathology, this peculiar conformational variant was caused by post-translational modifications rather than mutations as commonly observed in cancer. Although the presence of the conformational variant of p53 in the brain has yet to be formally demonstrated, the plethora of p53-dependent compensation mechanisms underscores that the guardian of the genome may not only be lost in the periphery during AD pathology.

Conclusion

These findings revisit the role of p53 in the early development and exacerbation of AD pathology, both in the brain and periphery. The conformational variant of p53 represents a potential peripheral biomarker that could detect AD at its earliest stages.
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Metadata
Title
The pleiotropic role of p53 in functional/dysfunctional neurons: focus on pathogenesis and diagnosis of Alzheimer’s disease
Authors
Giulia Abate
Giovanni B. Frisoni
Jean-Christophe Bourdon
Simona Piccirella
Maurizio Memo
Daniela Uberti
Publication date
01-12-2020
Publisher
BioMed Central
Published in
Alzheimer's Research & Therapy / Issue 1/2020
Electronic ISSN: 1758-9193
DOI
https://doi.org/10.1186/s13195-020-00732-0

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