Diadem Announces New Publication Reviewing How Post Translational Modifications of p53 Variants May Contribute to Development of Alzheimer’s Disease
—Post-Translational Modifications of Conformational Variants of p53 Appear to Impact Pathogenesis of Alzheimer’s Disease—
Study author Rakez Kayed, PhD, 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 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.
About Alzheimer’s Disease
There are about 50 million people suffering from dementia worldwide. Alzheimer’s disease is the most common form and accounts for 60-70% of cases. At present there are no disease modifying treatments for Alzheimer's, and therapies to treat symptoms are limited. There are about 10 million new cases per year, and the incidence is rising rapidly as the population ages. The current total cost of care is enormous--estimated at $1 trillion in the U.S. annually and expected to double by 2030. Currently, diagnosis of Alzheimer’s disease is slow, inconclusive, invasive and expensive. Development of effective therapies for Alzheimer’s has been hindered by the lack of accurate and cost-effective prognostic and diagnostic methods.
Diadem was founded as a spin-off of the University of Brescia (Italy). The company is developing the first blood-based prognostic test for the early detection of dementia, with a focus on Alzheimer’s disease. The lack of accurate, accessible and affordable diagnostic tools is a major contributor to the absence of effective treatments for this devastating condition. As a result, patients are not diagnosed until late in the illness, when effective treatment is no longer possible. Diadem’s rapid, accurate and cost-effective blood-based prognostic test makes it possible for the first time to identify patients early in the disease process, when effective interventions and better outcomes are far more feasible. The utility of the approach has been demonstrated in early clinical studies. Additional retrospective and prospective clinical trials are ongoing and planned to further validate clinical claims and support widespread adoption and use. Diadem’s founding lead investor is Milan-based Panakes Partners, a venture capital firm that finances promising high potential biomedical companies in Europe and Israel. Diadem is preparing for rapid commercialization of its initial Alzheimer’s prognostic via a global launch in collaboration with strategic partners. For more information, visit www.diademdx.com/.