Structural Transitions Associated with the Interaction of Alzheimer β-Amyloid Peptides with Gangliosides

Abstract

Alzheimer's disease is characterized pathologically by the presence of neurofibrillary tangles and amyloid plaques. The principal component of the plaque is the ␤-amyloid peptide (A␤), a 39 -43-residue peptide. The conformational change required for the conversion of soluble peptide into amyloid fibrils is modulated by pH, A␤ concentration, addition of kinetic and thermodynamic enhancers, and alterations in the primary sequence of A␤. We report here the ability of gangliosides to induce an ␣-helical structure in A␤ and thereby diminish fibrillogenesis. Circular dichroism and a fluorescence dye release assay data indicate that gangliosides interact with and induce ␣-helix formation in A␤. We find that the sialic acid moiety of gangliosides is necessary for the induction of ␣-helical structure. Differences in the amount and the position of the sialic acid on the carbohydrate backbone also affect the conformational switch. The A␤-ganglioside interaction at pH 7.0, monitored by CD, is stable over time and resistant to high concentrations of NaCl. The induction of ␣-helical structure is greater with A␤1-40 than A␤1-42. The ability of gangliosides to sequester A␤ from fibril formation was also evaluated by electron microscopy.Alzheimer's disease is characterized by the presence of amyloid plaques surrounded by dead and dying neurons in the brain (1, 2). The principal component of the plaque is the ␤-amyloid (A␤) 1 peptide, a 39 -43-residue peptide found in normal human tissue and generated as a cleavage product from the larger amyloid precursor protein (3)(4)(5)(6). A␤ in the plaque is in the form of an amyloid fibril, approximately 100 Å in diameter and several microns long (7). The conformational changes required for the conversion of soluble A␤ into amyloid fibrils have been demonstrated to be a nucleation-dependent process (8, 9) which is modulated by pH, A␤-peptide concentrations, and presence of nucleation seeds, such as proteoglycans and apolipoproteins (10 -14). Alterations in the primary sequence of A␤ peptides greatly affect amyloid fibril formation (15). The E22Q mutation in A␤, found in hereditary cerebral hemorrhage with amyloidosis of the dutch type (16), yields a peptide with increased ability to form amyloid fibrils (17). On the other hand, the single mutation of V18A increases the apparent ␣-helical content of A␤ and diminishes fibrillogenesis (18). We have found that the interaction of A␤40 and A␤42 with mixed ganglioside preparations and GM1 increases the ␣-helical content, and we speculated that this interaction may prevent amyloid fibril formation (19).It has been well documented that amyloid fibrils are intimately associated with neuronal, microglial, and endothethial membranes. Cell processes are extended out into close proximity of amyloid deposits (20,21), and cell culture studies have demonstrated that overexpression of A␤ results in cell surface ruffling (22-24). These results, as well as the studies on A␤-membrane interactions (19,(25)(26)(27)(28)(29)(30)(31), suggested that the interaction...

A Seed for Alzheimer Amyloid in the Brain

“…On the basis of the molecular characteristics of the GM1-bound A␤ (GA␤), including its altered immunoreactivity and a strong tendency to form aggregates of A␤, we hypothesized that A␤ adopts an altered conformation by binding to GM1 and initiates the aggregation of soluble A␤ by acting as a seed (Yanagisawa et al, 1995(Yanagisawa et al, , 1997Yanagisawa and Ihara, 1998). Evidence that supports our hypothesis is growing from in vitro studies by our group and other groups (McLaurin and Chakrabartty, 1996;McLaurin et al, 1998;Matsuzaki and Horikiri, 1999;Ariga et al, 2001;Kakio et al, 2001Kakio et al, , 2002.…”

Sugar microarray via click chemistry: molecular recognition with lectins and amyloid β (1–42)

“…That is, Aβ showed the β-sheet conformation on the saccharide, which showed stronger affinities to Aβ. These results suggested that the sulfonated saccharides in glycosaminoglycans and sialic acid in ganglioside are related to the amyloidosis of peptides [17,18].…”

“…GM1 interacts with Aβ to induce fibril formation [17,18]. Interestingly, GM1 displays Gal and sialic acid at the nonreducing terminal.…”

“…It has been reported that several types of saccharide interact with Aβ [17][18][19]. GM1 interacts with Aβ to induce fibril formation [17,18].…”

“…We particularly focused on the interaction between amyloid β peptide (Aβ) and observed fibril formation on a specific saccharide. It has been reported that the saccharide-protein interaction is related to Alzheimer disease and amyloidosis of Aβ; for example, ganglioside GM1 [17,18] and glycosaminoglycans [19] are related to Aβ amyloidosis. However, no detailed analyses of saccharide-protein interaction associated with amyloidosis of Aβ were conducted.…”