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

Ganglioside GM1 is the most common brain ganglioside enriched in plasma membrane regions known as lipid rafts or membrane microdomains. GM1 participates in many modulatory and communication functions associated with the development, differentiation, and protection of neuronal tissue. It has, however, been demonstrated that GM1 plays a negative role in the pathophysiology of Alzheimer's disease (AD). The two features of AD are the formation of intracellular neurofibrillary bodies and the accumulation of extracellular amyloid β (Aβ). Aβ is a peptide characterized by intrinsic conformational flexibility. Depending on its partners, Aβ can adopt different spatial arrangements. GM1 has been shown to induce specific changes in the spatial organization of Aβ, which lead to enhanced peptide accumulation and deleterious effect especially on neuronal membranes containing clusters of this ganglioside. Changes in GM1 levels and distribution during the development of AD may contribute to the aggravation of the disease.

• Klíčová slova
• Alzheimer’s disease, GM1, amyloid oligomers, amyloid β, fibrils, gangliosides, membrane microdomains,
• Publikační typ
• časopisecké články MeSH
• přehledy 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

Alzheimer's disease (AD) is the most common form of dementia. The risk of AD increases with age. Although two of the main pathological features of AD, amyloid plaques and neurofibrillary tangles, were already recognized by Alois Alzheimer at the beginning of the 20th century, the pathogenesis of the disease remains unsettled. Therapeutic approaches targeting plaques or tangles have not yet resulted in satisfactory improvements in AD treatment. This may, in part, be due to early-onset and late-onset AD pathogenesis being underpinned by different mechanisms. Most animal models of AD are generated from gene mutations involved in early onset familial AD, accounting for only 1% of all cases, which may consequently complicate our understanding of AD mechanisms. In this article, the authors discuss the pathogenesis of AD according to the two main neuropathologies, including senescence-related mechanisms and possible treatments using stem cells, namely mesenchymal and neural stem cells.

• Klíčová slova
• Alzheimer’s disease, Tau, amyloid-β, mesenchymal stem cells, neural stem cells,
• MeSH
• Alzheimerova nemoc etiologie   metabolismus   patologie   terapie   MeSH
• amyloidní beta-protein imunologie   metabolismus   MeSH
• amyloidní plaky metabolismus   patologie   MeSH
• buněčná a tkáňová terapie * metody   MeSH
• energetický metabolismus MeSH
• imunoterapie metody   MeSH
• kmenové buňky cytologie   metabolismus   MeSH
• lidé MeSH
• modely nemocí na zvířatech MeSH
• mutace MeSH
• neuroglie metabolismus   MeSH
• proteiny tau imunologie   metabolismus   MeSH
• stárnutí genetika   imunologie   metabolismus   MeSH
• transplantace kmenových buněk metody   MeSH
• věk při počátku nemoci MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• amyloidní beta-protein MeSH
• proteiny tau MeSH