Speaker
Description
Alzheimer’s disease is a progressive neurodegenerative disorder characterized by the irreversible loss of neurons. Under normal conditions, ATM proteins exist as inactive homodimers in the cytoplasm. When oxidative stress occurs, these dimers dissociate into monomers that migrate to the nucleus, where they detect and repair double-strand DNA breaks. However, recent findings indicate that in all cells from Alzheimer’s patients, the ApoE protein, overexpressed and abnormally clustered around the nucleus, binds to ATM monomers. This interaction traps ATM–ApoE heterodimers at the nuclear envelope. As a consequence, the remaining ATM monomers, present at unusually high concentrations, rapidly re-dimerize before reaching the nucleus. These retained dimers accumulate at the perinuclear region, leading to the formation of a distinctive perinuclear crown. To better understand the mechanisms underlying this phenomenon and to explore potential therapeutic strategies, we developed two complementary modeling approaches: a compartmental model and a reaction–diffusion system that describes the physical and biochemical interactions between ATM and ApoE proteins. Both models integrate key processes such as protein transport, monomer aggregation, dimer and complex dissociation, and spatial constraints at the nuclear envelope. Using these models, we investigated how irradiation and antioxidant treatments influence the disintegration of the perinuclear crown. Our simulations show that while each strategy alone has a measurable effect, their combined application is significantly more effective in delaying or preventing the reformation of the crown. This synergy points toward a promising therapeutic direction for mitigating cellular dysfunction in Alzheimer’s disease.
