Abstract

Age-related neurodegenerative diseases (NDDs), such as Alzheimer's and Parkinson's, are characterized by progressive neuronal dysfunction and loss. Emerging evidence highlights the critical, yet often overlooked, role of cellular membranes in the pathogenesis of these disorders. This study investigates the hypothesis that alterations in the physical properties and organization of neuronal membranes, specifically the formation and stability of lipid domains (e.g., lipid rafts), contribute significantly to NDD development. Using a combination of advanced biophysical techniques, including fluorescence spectroscopy and atomic force microscopy on model and native neuronal membranes, we analyzed changes in membrane fluidity, lipid packing, and domain size in response to age-mimicking stressors. Our key findings demonstrate a significant decrease in membrane fluidity and a disruption of lipid raft integrity in aged membrane samples, correlating with increased aggregation of amyloidogenic proteins. These physical changes impair critical membrane-associated processes, such as receptor signaling and ion homeostasis, which are central to neuronal health. The results underscore the importance of maintaining optimal membrane biophysical properties and lipid domain organization as a potential therapeutic target for mitigating the progression of age-related neurodegenerative diseases.