The Role of Lipid Environment in Ganglioside GM1-Induced Amyloid β Aggregation

Abstract

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.

Figure 1

Amyloid β oligomerization. After processing of amyloid precursor protein (APP) by secretase enzymes, Aβ monomers are released into the intercellular space. In dependence on the environment, Aβ form and concentration, monomers may aggregate into supramolecular structures including low and high-molecular clusters. Among them, the 56 kDa Aβ dodecamers show the highest extent of neurotoxicity. Amyloid oligomers may form either globular, or fibrillar conglomerations known as protofibrils and fibrils. Membrane bound fibrils organize into amyloid plaques. Aβ clustering and fragmentation are reversible processes, so mutual interconversions between particular forms occur.

Figure 2

β-Sheet-containing forms of amyloid β. In dependence on the environment and peptide concentration, Aβ may organize into distinct combinations of β-rich tertiary and quaternary structures. (A) β-hairpin; (B) parallel β-hairpin structure. Particular peptides are interconnected through non-covalent interactions; (C) antiparallel arrangement, characteristic for toxic oligomers of amyloid peptide; (D) different mutual positions of internal β-sheets result from rotation of the upper part of the amyloid peptide; (E) an extended conformation of β-sheets containing amyloid monomer; (F) structure of amyloid fibril with parallel orientation of Aβ monomers. (G) Supposed organization of a trimer; (H) organization of a fiber formed of trimers. Many other possibilities of fibrillar and globular aggregates including pentamers and hexamers were described, but are not shown here. Adjusted according to [39,41,61,74].

Figure 3

Aggregation of amyloid β on GM1-containing membrane. After processing of APP, Aβ (red) is released into intercellular space. Certain membrane molecules, including ganglioside GM1, serve as nucleation centers for Aβ aggregation. (1) Binding to non-clustered GM1 induces α-helical conformation in Aβ. (2) GM1 causes transition of α-helical to β-sheet structure. (3) Clusters of GM1 localized to membrane microdomains are responsible for concentration and aggregation of amyloid peptide into higher-molecular forms. Both parallel and antiparallel β-structures were observed in membrane bound amyloid fibrils. (4) Aggregates of Aβ serve as platforms for capturing and binding of monomers or oligomers circulating in the intercellular space. On the other hand, some portion of amyloid peptides may release from the aggregates (5). Adjusted according to [66,85,92,153,155].