The MAHATMA project
Alzheimer’s disease (AD) is currently the most common cause of neurocognitive disorder. Its diagnosis relies on clinical symptoms, brain imaging, and the analysis of pathophysiological biomarkers associated with the amyloid plaque deposits and tau protein aggregates that characterize the disease. Despite considerable efforts, these approaches have not yet led to curative treatments.
In 2023, UMR 1296 Inserm demonstrated that skin fibroblasts from Alzheimer’s disease (AD) patients are characterized by the clustering of the ATM protein around the cell nucleus. ATM plays a key role in DNA damage signaling. In response to a latent, persistent stress—thought to be specific to many neurodegenerative diseases—ATM moves toward the nucleus to trigger the repair of DNA breaks. In AD patient fibroblasts, the overexpression of APOE around the nucleus appears to facilitate the formation of perinuclear ATM rings by associating with the ATM protein; this process is considered a major step in cellular aging.
In fibroblasts from AD patients, APOE protein overexpressed around the nucleus appears to facilitate the formation of perinuclear ATM rings by associating with the ATM protein—a process that constitutes a major step in cellular aging.
A multidisciplinary consortium
Results concerning these perinuclear ATM rings have been published, supported by an initial mathematical model, and protected by a patent filed in early 2023. However, these preliminary data are derived from only 10 AD patients. The goal of the MAHATMA project is therefore to consolidate and validate the hypothesis that ATM-APOE perinuclear rings are specific biomarkers for AD, by studying 40 new AD cases and 40 matched, disease-free controls.
An in-depth study will also be conducted on genotoxic stressors capable of accelerating the process of ATM clustering around the cell nucleus. The MAHATMA project is inherently multidisciplinary, involving radiobiologists (INSERM), mathematicians (LYON 1), clinical neurologists and geriatricians (HCL), and biologists (HCL) specializing in the diagnosis and management of AD.
Project leaders:
Nicolas FORAY
Nicolas Foray is a radiobiologist and INSERM Research Director with extensive experience in the field of individual response to ionizing radiation. He notably directs the INSERM UMR1296 unit dedicated to radiation effects research and coordinates a national radiobiology project (part of the “Investments for the Future” program) focused on individual radiosensitivity.
He has also served as a coordinator or partner for several radiobiological studies over the past 20 years, at European, national, and regional levels. He has published over 150 peer-reviewed articles and around ten book chapters, and is the author of four books. He served as president of the Société Francophone de Radiobiologie (Francophone Radiobiology Society) for eight years and as editor-in-chief of the *International Journal of Low Radiation* from 2011 to 2021. He authored an article for The Conversation titled “Alzheimer : une nouvelle explication généralisable à toute maladie liée au vieillissement ?”.
Laurent PUJO-MENJOUET
Laurent Pujo-Menjouet is a Professor of Applied Mathematics at the Institut Camille Jordan, Lyon 1 Université. His research focuses on the mathematical modeling of various biomedical issues, notably neurodegenerative diseases (prion diseases, Alzheimer’s disease), blood regulation and associated pathologies such as leukemia, as well as the epidemiology of infectious diseases (influenza, COVID-19, HIV).
He is also interested in the modeling of bone formation, social dynamics (the evolution of endangered languages, dietary behaviors, romantic relationships), and radiobiology. His approach relies on deterministic models primarily employing ordinary differential equations, partial differential equations, and delay differential equations.
Partners
Virginie DESESTRET
Virginie Desestret is a neurologist and a University Professor-Hospital Practitioner (PU-PH) specializing in histology. Working within the Neuro-cognition and Neuro-ophthalmology Department at hôpital P. Wertheimer and as part of the Centre Mémoire Ressource Recherche of the Hospices Civils de Lyon, she treats patients with neurocognitive disorders—primarily of neurodegenerative, autoimmune, and iatrogenic origin. She is developing a clinical and translational research program focused on the cognitive impact of anti-cancer therapies, particularly immunotherapies and targeted therapies.
As part of the MeLiS team (INSERM U1314 / UMR CNRS 5284), she conducts mechanistic research into the pathophysiology of paraneoplastic neurological syndromes, based on histo-molecular analysis of both tumor and brain tissue. The aim is to understand the mechanisms behind the breakdown of immune tolerance that triggers the autoimmune disease, as well as its impact on brain function, particularly cognitive function.
Antoine GARNIER-CRUSSARD
Antoine Garnier-Crussard is a geriatrician and University Hospital Practitioner (MCU-PH) at the Centre Mémoire Ressource Recherche of the Hospices Civils de Lyon and Lyon 1 Université, specializing in Alzheimer’s disease and related disorders. His research spans several areas aimed at better understanding the origins of cognitive impairment, loss of autonomy, and neuropsychiatric symptoms associated with aging and neurocognitive disorders. He investigates both degenerative and vascular brain lesions (using imaging and fluid biomarkers) and “systemic” factors linked to cognitive impairment (such as frailty, multimorbidity, and anticholinergic medications), as well as the interplay between them.
He is the Medical Director of the Centre de Recherche Clinique Vieillissement-Cerveau-Fragilité (CRC VCF), a facility dedicated to project development and clinical research on various topics related to aging, including conducting drug-based therapeutic trials for Alzheimer’s disease.
