A comparative analysis of the aggregation behavior of amyloid-β peptide variants.

Aggregated forms of the amyloid-β peptide are hypothesized to act as the prime toxic agents in Alzheimer disease (AD). The in vivo amyloid-β peptide pool consists of both C- and N-terminally truncated or mutated peptides, and the composition thereof significantly determines AD risk. Other variations, such as biotinylation, are introduced as molecular tools to aid the understanding of disease mechanisms.

Molecular plasticity regulates oligomerization and cytotoxicity of the multipeptide-length amyloid-β peptide pool.

Current therapeutic approaches under development for Alzheimer disease, including γ-secretase modulating therapy, aim at increasing the production of Aβ(1-38) and Aβ(1-40) at the cost of longer Aβ peptides. Here, we consider the aggregation of Aβ(1-38) and Aβ(1-43) in addition to Aβ(1-40) and Aβ(1-42), in particular their behavior in mixtures representing the complex in vivo Aβ pool. We demonstrate that Aβ(1-38) and Aβ(1-43) aggregate similar to Aβ(1-40) and Aβ(1-42), respectively, but display a variation in the kinetics of assembly and toxicity due to differences in short timescale conformational plasticity.

The mechanism of γ-Secretase dysfunction in familial Alzheimer disease.

The mechanisms by which mutations in the presenilins (PSEN) or the amyloid precursor protein (APP) genes cause familial Alzheimer disease (FAD) are controversial. FAD mutations increase the release of amyloid β (Aβ)42 relative to Aβ40 by an unknown, possibly gain-of-toxic-function, mechanism. However, many PSEN mutations paradoxically impair γ-secretase and 'loss-of-function' mechanisms have also been postulated.

Structural basis for increased toxicity of pathological aβ42:aβ40 ratios in Alzheimer disease.

The β-amyloid peptide (Aβ) is directly related to neurotoxicity in Alzheimer disease (AD). The two most abundant alloforms of the peptide co-exist under normal physiological conditions in the brain in an Aβ(42):Aβ(40) ratio of ∼1:9. This ratio is often shifted to a higher percentage of Aβ(42) in brains of patients with familial AD and this has recently been shown to lead to increased synaptotoxicity.

A standardized and biocompatible preparation of aggregate-free amyloid beta peptide for biophysical and biological studies of Alzheimer's disease.

We provide a validated and rapid protocol for the solubilization of amyloid β-peptide (Aβ). This procedure involves sequential solubilization using structure-breaking organic solvents hexafluoroisopropanol and DMSO followed by column purification. The low solubility and tendency of Aβ to aggregate considerably impede the in vitro handling and biophysical or biological investigation of Aβ, despite the interest in this peptide because of its implication in Alzheimer's disease.

Amyloid precursor protein mutation E682K at the alternative β-secretase cleavage β'-site increases Aβ generation.

BACE1 cleaves the amyloid precursor protein (APP) at the β-cleavage site (Met(671) -Asp(672) ) to initiate the generation of amyloid peptide Aβ. BACE1 is also known to cleave APP at a much less well-characterized β'-cleavage site (Tyr(681) -Glu(682) ). We describe here the identification of a novel APP mutation E682K located at this β'-site in an early onset Alzheimer's disease (AD) case.

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

The amyloid peptides Aβ(40) and Aβ(42) of Alzheimer's disease are thought to contribute differentially to the disease process. Although Aβ(42) seems more pathogenic than Aβ(40), the reason for this is not well understood. We show here that small alterations in the Aβ(42):Aβ(40) ratio dramatically affect the biophysical and biological properties of the Aβ mixtures reflected in their aggregation kinetics, the morphology of the resulting amyloid fibrils and synaptic function tested in vitro and in vivo.