*Article* **Effect of Amyloid-β Monomers on Lipid Membrane Mechanical Parameters–Potential Implications for Mechanically Driven Neurodegeneration in Alzheimer's Disease**

**Dominik Drabik 1,\*, Grzegorz Chodaczek 2 and Sebastian Kraszewski 3**


**Abstract:** Alzheimer's disease (AD) is a neurodegenerative disease that results in memory loss and the impairment of cognitive skills. Several mechanisms of AD's pathogenesis were proposed, such as the progressive accumulation of amyloid-β (Aβ) and τ pathology. Nevertheless, the exact neurodegenerative mechanism of the Aβ remains complex and not fully understood. This paper proposes an alternative hypothesis of the mechanism based on maintaining the neuron membrane's mechanical balance. The incorporation of Aβ decreases the lipid membrane's elastic properties, which eventually leads to the impairment of membrane clustering, disruption of mechanical wave propagation, and change in gamma oscillations. The first two disrupt the neuron's ability to function correctly while the last one decreases sensory encoding and perception enabling. To begin discussing this mechanical-balance hypothesis, we measured the effect of two selected peptides, Aβ-40 and Aβ-42, as well as their fluorescently labeled modification, on membrane mechanical properties. The decrease of bending rigidity, consistent for all investigated peptides, was observed using molecular dynamic studies and experimental flicker-noise techniques. Additionally, wave propagation was investigated with molecular dynamic studies in membranes with and without incorporated neurodegenerative peptides. A change in membrane behavior was observed in the membrane system with incorporated Aβ.

**Keywords:** membrane mechanics; molecular dynamics; flicker-noise spectroscopy; neurodegeneration; amyloid-beta peptides; pressure wave; giant unilamellar vesicles
