Neurotoxicity of Alzheimer's disease Aβ peptides is induced by small changes in the Aβ42 to Aβ40 ratio

Abstract

The amyloid peptides Ab 40 and Ab 42 of Alzheimer's disease are thought to contribute differentially to the disease process. Although Ab 42 seems more pathogenic than Ab 40 , the reason for this is not well understood. We show here that small alterations in the Ab 42 :Ab 40 ratio dramatically affect the biophysical and biological properties of the Ab mixtures reflected in their aggregation kinetics, the morphology of the resulting amyloid fibrils and synaptic function tested in vitro and in vivo. A minor increase in the Ab 42 :Ab 40 ratio stabilizes toxic oligomeric species with intermediate conformations. The initial toxic impact of these Ab species is synaptic in nature, but this can spread into the cells leading to neuronal cell death. The fact that the relative ratio of Ab peptides is more crucial than the absolute amounts of peptides for the induction of neurotoxic conformations has important implications for anti-amyloid therapy. Our work also suggests the dynamic nature of the equilibrium between toxic and non-toxic intermediates.

Biometals and Their Therapeutic Implications in Alzheimer's Disease

“…Traditionally, it was believed that Aβ1-42 is predominately responsible for toxicity observed in AD. Two key observations support this theory: 1) familial AD mutations in APP elevate the expression of Aβ1-42 [24,25]; and 2) Aβ1-42 is more prone to aggregation and is more toxic than Aβ1-40 [26,27]. However, it was reported that pyroglutamate-Aβ, which is also presented in AD plaques, could also be the toxic isoform of Aβ [28][29][30][31].…”

Characterization of Oligomer Formation of Amyloid-β Peptide Using a Split-luciferase Complementation Assay

“…We cannot rule out the possibility that this result is secondary to the structure of the split Gluc constructs, but Shanker et al (10) report, using endogenous A␤, that heterodimers are rare. Recently A␤ oligomers made by a mixture of synthetic A␤40 and A␤42 (ratio 7:3) was found to be more stable and neurotoxic compared with A␤40 or A␤42 solo oligomer (32). A␤40 and A␤42 is also reported to coassemble into amyloid fibrils (33,34), suggesting that A␤40 or A␤42 homo oligomer may be mixed and may form further aggregated structures.…”

Alzheimer Presenilin-1 Mutations Dramatically Reduce Trimming of Long Amyloid β-Peptides (Aβ) by γ-Secretase to Increase 42-to-40-Residue Aβ

“…Our findings are consistent with recent reports suggesting that FAD-mutant presenilins can cause a reduction in the conversion of A␤43 and A␤42 to A␤40 and A␤38, respectively (7,25). This loss of carboxypeptidase function results in a gain of function; that is, the elevation of the critical A␤42/A␤40, thereby increasing the propensity of A␤ to aggregation and neurotoxicity (36). It should be noted that this specific loss of function also elevates longer A␤ peptides (7,14) and that the gain of neurotoxic function may be through these forms of A␤.…”