Amyloid-beta aggregation: selective inhibition of aggregation in mixtures of amyloid with different chain lengths

Abstract

One of the clinical manifestations of Alzheimer's disease is the deposition of the 39-43 residue amyloid-beta (A beta) peptide in aggregated fibrils in senile plaques. Characterization of the aggregation behavior of A beta is one of the critical issues in understanding the role of A beta in the disease process. Using solution hydrodynamics, A beta was observed to form three types of species in phosphate-buffered saline: insoluble aggregates with sedimentation coefficients of approximately 50,000 S and molecular masses of approximately 10(9) Da, "soluble aggregates" with sedimentation coefficients of approximately 30 S and masses of approximately 10(6) Da, and monomer. When starting from monomer, the aggregation kinetics of A beta 1-40 (A beta 40) and A beta 1-42 (A beta 42), alone and in combination, reveal large differences in the tendency of these peptides to aggregate as a function of pH and other solution conditions. At pH 4.1 and 7.0-7.4, aggregation is significantly slower than at pH 5 and 6. Under all conditions, aggregation of the longer A beta 42 was more rapid than A beta 40. Oxidation of Met-35 to the sulfoxide in A beta 40 enhances the aggregation rate over that of the nonoxidized peptide. Aggregation was found to be dependent upon temperature and to be strongly dependent on peptide concentration and ionic strength, indicating that aggregation is driven by a hydrophobic effect. When A beta 40 and A beta 42 are mixed together, A beta 40 retards the aggregation of A beta 42 in a concentration-dependent manner. Shorter fragments have a decreasing ability to interfere with A beta 42 aggregation. Conversely, the rate of aggregation of A beta 40 can be significantly enhanced by seeding slow aggregating solutions with preformed aggregates of A beta 42. Taken together, the inhibition of A beta 42 aggregation by A beta 40, the seeding of A beta 40 aggregation by A beta 42 aggregates, and the chemical oxidation of A beta 40 suggest that the relative abundance and rates of production of different-length A beta and its exposure to radical damage may be factors in the accumulation of A beta in plaques in vivo.

A comparative analysis of the aggregation behavior of amyloid‐β peptide variants

“…Our observations show that variations in the Ab sequence can have consequences for the propensity of the Ab peptide to aggregate and oligomerize. C-terminal variation was previously shown to affect aggregation propensity, and it has been generally reported that Ab aggregates at a higher rate than Ab 1-40 [20,21]. Even though approximately 90% of the Ab peptide pool is composed of these two peptides, it was recently recognized that also Ab 1-37 , Ab , and Ab are present in the brain and may modulate disease progress [22].…”

The human β-amyloid precursor protein: biomolecular and epigenetic aspects

“…The Aβ peptides vary in size from 39 to 42 amino acids, and Aβ 1−42 aggregates more readily than the other molecules (35). A GxxxG sequence motif within the transmembrane domain has been implicated in homodimerization (36) and in cholesterol-binding (37) (Figure 1B).…”

Preparation and characterization of toxic Aβ aggregates for structural and functional studies in Alzheimer's disease research

“…Quasielastic light-scattering measurements revealed that SEC-purified Aβ protofibrils contained aggregates with hydrodynamic radii (R H ) of 10-50 nm, which correspond to lengths of ~30-500 nm for noninteracting rods 13 . The heterogeneity of protofibrils was further elucidated by scanning transmission electron microscopy (TEM) 18 and sedimentation velocity measurements 57 . These studies revealed that protofibrils are a population of aggregates with molecular weight distribution ranging from 80 kDa to ~1 mDa (ref.…”

“…Although these preparations are free of protofibrillar or fibrillar aggregates, the presence of unstable LMW oligomers (dimers, trimers, and so on) that are in rapid equilibrium with the major monomeric species has been suggested and cannot be ruled out. To prepare protofibrillar Aβ fractions, the peptide is initially dissolved in DMSO 57 and then aggregation is promoted under high-salt conditions. This leads to the generation of a solution enriched with Aβ protofibrils and monomers.…”