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.

• Keywords
• Alzheimer’s disease, GM1, amyloid β, cholesterol, lipid rafts, lipids, membrane,
• Publication type
• Journal Article MeSH
• Review 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.

• Keywords
• Alzheimer’s disease, GM1, amyloid oligomers, amyloid β, fibrils, gangliosides, membrane microdomains,
• Publication type
• Journal Article MeSH
• Review MeSH

Allosteric modulators are ligands that bind to a site on the receptor that is spatially separated from the orthosteric binding site for the endogenous neurotransmitter. Allosteric modulators modulate the binding affinity, potency, and efficacy of orthosteric ligands. Muscarinic acetylcholine receptors are prototypical allosterically-modulated G-protein-coupled receptors. They are a potential therapeutic target for the treatment of psychiatric, neurologic, and internal diseases like schizophrenia, Alzheimer's disease, Huntington disease, type 2 diabetes, or chronic pulmonary obstruction. Here, we reviewed the progress made during the last decade in our understanding of their mechanisms of binding, allosteric modulation, and in vivo actions in order to understand the translational impact of studying this important class of pharmacological agents. We overviewed newly developed allosteric modulators of muscarinic receptors as well as new spin-off ideas like bitopic ligands combining allosteric and orthosteric moieties and photo-switchable ligands based on bitopic agents.

• Keywords
• acetylcholine, allosteric modulation, muscarinic receptors,
• MeSH
• Muscarinic Agonists metabolism   MeSH
• Allosteric Regulation physiology   MeSH
• Muscarinic Antagonists metabolism   MeSH
• Humans MeSH
• Ligands MeSH
• Receptors, Muscarinic metabolism   physiology   MeSH
• Receptors, G-Protein-Coupled MeSH
• Binding Sites MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH
• Names of Substances
• Muscarinic Agonists MeSH
• Muscarinic Antagonists MeSH
• Ligands MeSH
• Receptors, Muscarinic MeSH
• Receptors, G-Protein-Coupled MeSH