Alzheimer's disease (AD) is a neurodegenerative disorder that is one of the most devastating and widespread diseases worldwide, mainly affecting the aging population. One of the key factors contributing to AD-related neurotoxicity is the production and aggregation of amyloid β (Aβ). Many studies have shown the ability of Aβ to bind to the cell membrane and disrupt its structure, leading to cell death. Because amyloid damage affects different parts of the brain differently, it seems likely that not only Aβ but also the nature of the membrane interface with which the amyloid interacts, helps determine the final neurotoxic effect. Because cholesterol is the dominant component of the plasma membrane, it plays an important role in Aβ-induced toxicity. Elevated cholesterol levels and their regulation by statins have been shown to be important factors influencing the progression of neurodegeneration. However, data from many studies have shown that cholesterol has both neuroprotective and aggravating effects in relation to the development of AD. In this review, we attempt to summarize recent findings on the role of cholesterol in Aβ toxicity mediated by membrane binding in the pathogenesis of AD and to consider it in the broader context of the lipid composition of cell membranes.

• Klíčová slova
• Alzheimer’s disease, GM1, amyloid β, cholesterol, lipid rafts, lipids, membrane,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

The fluorescent molecule diphenylhexatriene (DPH) has been often used in combination with fluorescence anisotropy measurements, yet little is known regarding the non-linear optical properties. In the current work, we focus on them and extend the application to fluorescence, while paying attention to the conformational versatility of DPH when it is embedded in different membrane phases. Extensive hybrid quantum mechanics/molecular mechanics calculations were performed to investigate the influence of the phase- and temperature-dependent lipid environment on the probe. Already, the transition dipole moments and one-photon absorption spectra obtained in the liquid ordered mixture of sphingomyelin (SM)-cholesterol (Chol) (2:1) differ largely from the ones calculated in the liquid disordered DOPC and solid gel DPPC membranes. Throughout the work, the molecular conformation in SM:Chol is found to differ from the other environments. The two-photon absorption spectra and the ones obtained by hyper-Rayleigh scattering depend strongly on the environment. Finally, a stringent comparison of the fluorescence anisotropy decay and the fluorescence lifetime confirm the use of DPH to gain information upon the surrounding lipids and lipid phases. DPH might thus open the possibility to detect and analyze different biological environments based on its absorption and emission properties.

• Klíčová slova
• QM/MM, absorption, conformationally versatile molecules, fluorescence anisotropy, fluorescence decay, hyper-Rayleigh scattering, photoselection, two-photon absorption,
• MeSH
• cholesterol chemie   MeSH
• difenylhexatrien chemie   MeSH
• fluorescenční barviva chemie   MeSH
• fluorescenční polarizace MeSH
• lipidové dvojvrstvy chemie   MeSH
• molekulární konformace MeSH
• sfingomyeliny chemie   MeSH
• simulace molekulární dynamiky MeSH
• tranzitní teplota MeSH
• vztahy mezi strukturou a aktivitou MeSH
• změna skupenství MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• cholesterol MeSH
• difenylhexatrien MeSH
• fluorescenční barviva MeSH
• lipidové dvojvrstvy MeSH
• sfingomyeliny MeSH

β-Amyloid (Aβ) oligomers are neurotoxic and implicated in Alzheimer's disease. Neuronal plasma membranes may mediate formation of Aβ oligomers in vivo. Membrane components sphingomyelin and GM1 have been shown to promote aggregation of Aβ; however, these studies were performed under extreme, non-physiological conditions. We demonstrate that physiological levels of GM1 , organized in nanodomains do not seed oligomerization of Aβ40 monomers. We show that sphingomyelin triggers oligomerization of Aβ40 and that GM1 is counteractive thus preventing oligomerization. We propose a molecular explanation that is supported by all-atom molecular dynamics simulations. The preventive role of GM1 in the oligomerization of Aβ40 suggests that decreasing levels of GM1 in the brain, for example, due to aging, could reduce protection against Aβ oligomerization and contribute to the onset of Alzheimer's disease.

• Klíčová slova
• Alzheimer's disease, amyloid beta-peptides, diffusion coefficients, fluorescence spectroscopy, neuroprotectives,
• MeSH
• amyloidní beta-protein antagonisté a inhibitory   metabolismus   MeSH
• G(M1) gangliosid chemie   farmakologie   MeSH
• sfingomyeliny chemie   farmakologie   MeSH
• simulace molekulární dynamiky MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• amyloidní beta-protein MeSH
• G(M1) gangliosid MeSH
• sfingomyeliny MeSH