New publication reviews how post translational modifications of p53 may contribute to the development of Alzheimer’s disease

Diadem srl, a company developing the first blood-based test for the early prediction of progression to Alzheimer’s disease (AD), has announced the release of a new publication, Post-Translational Modifications of the p53 Protein and the Impact in Alzheimer’s Disease, that reviews how post translational modifications (PTMs) of the p53 protein may impact the development of Alzheimer’s disease. Diadem is developing the AlzoSure® Predict assay as a simple, non-invasive plasma-based biomarker test to accurately predict whether a patient with asymptomatic mild cognitive impairment will progress to Alzheimer’s dementia. The company’s technology uses an analytical method that measures blood levels of an unfolded conformational variant of the p53 protein that has been implicated in the pathogenesis of AD.

Study author Rakez Kayed, Ph.D., Professor and John Sealy Chair for Parkinson's Research at the Mitchell Center for Neurodegenerative Disorders of the University of Texas Medical Branch at Galveston, commented, “The growing understanding of the complex pathogenesis of Alzheimer’s disease is essential to developing effective diagnostics and therapeutics for this devastating condition. Increasing evidence suggests that certain conformational variants and post translational modifications of p53, well known for its role in cancer, may significantly impact the development of AD. This review aims to summarize what researchers have uncovered to date about the transformation of p53 into variants and PTMs that impact amyloid, tau, and other pathways implicated in the neurodegenerative processes that ultimately result in symptomatic AD. This knowledge is already fueling the creation of novel prognostic tests for AD and may lead to the development of new therapies to counter disease progression.”

This review article follows a study published last year in Alzheimer’s Research & Therapy that highlighted how dysregulated p53 activity may contribute to changes in the brain and peripheral nervous system during the early stages of AD. The review described how p53 dysregulation may exacerbate AD pathology by interfering with a variety of defense mechanisms that protect neurons and prevent their degeneration.
In the new publication, the authors note that the p53 protein, known as “the guardian of the genome”, has gained attention for its possible involvement in the early evolution of AD. p53 has many diverse roles in maintaining cellular function and any change in the protein’s functional activity greatly affects its downstream processes. P53 is involved in the regulation of oxidative stress, which is implicated as one of the earliest events in AD. The authors point to growing evidence that oxidative stress is a critical factor in AD initiation and progression, with a strong relationship to Aβ and tau-induced neurotoxicity, forming feedback loops that accelerate AD progression.

They discuss how post-translational modifications represent the most widespread and effective type of cellular mechanism controlling p53 function. PTMs affect the conformation of p53, increasing its capacity for adoption of multiple structural and functional states. These include both functional dysregulation and loss of function in cellular response pathways, with a number of these implicated in the development of AD. The authors also cite multiple studies showing that the conformational unfolding of p53 impacts its role, directly increasing or decreasing the activation of specific AD-associated pathways. They conclude that a significant amount of evidence supports the potential role of p53 PTMs in AD pathogenesis, and recommend further studies to further elucidate the mechanisms of action for specific PTMs and their involvement in the development of AD.

Paul Kinnon, CEO of Diadem, noted, “Decades of research on the role of p53 conformational variants in the development of AD are the foundation for our AlzoSure blood-based test for the early prediction of progression to AD. This new review adds to the growing evidence that certain biochemical reactions impact the loss of p53 function via post translational modifications to the linear sequence of the protein, resulting in upstream and downstream effects on amyloid and tau metabolism, as well as on other pathways involved in AD pathogenesis. It supports the results of our clinical studies showing that AlzoSure Predict can identify individuals who will progress to Alzheimer’s dementia up to six years before the disease is symptomatic.”

Diadem is developing the AlzoSure® Predict assay as a simple, non-invasive plasma-based biomarker test to accurately predict the probability that a patient with asymptomatic mild cognitive impairment will progress to Alzheimer’s dementia. The company’s technology uses an analytical method that includes a proprietary antibody developed by Diadem designed to bind to the conformational variant U-p53AZ protein and its target sequences. Diadem researchers recently published a retrospective longitudinal study of AlzoSure® Predict that confirmed it accurately identifies individuals with no or only minor cognitive impairments who will progress to fully symptomatic Alzheimer’s disease up to six years before dementia symptoms are evident.
The company is conducting a follow-up study using additional longitudinal data from different cohorts and centers in Europe and the U.S. to validate these findings and compare and correlate the potential of U-p53AZ as a blood-based biomarker with traditionally studied markers of AD pathology. Results are expected later this year.

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