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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(More)
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(More)
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(More)
Since the reformulation of the amyloid cascade hypothesis to focus on oligomeric aggregates of amyloid beta as the prime toxic species causing Alzheimer's disease, many researchers refocused on detecting a specific molecular assembly of defined size thatis the main trigger of Alzheimer's disease. The result has been the identification of a host of molecular(More)
Syntaxin and Munc18 are, in tandem, essential for exocytosis in all eukaryotes. Recently, it was shown that Munc18 inhibition of neuronal syntaxin 1 can be overcome by arachidonic acid, indicating that this common second messenger acts to disrupt the syntaxin-Munc18 interaction. Here, we show that arachidonic acid can stimulate syntaxin 1 alone, indicating(More)
Inna Kuperstein, Kerensa Broersen, Iryna Benilova, Jef Rozenski, Wim Jonckheere, Maja Debulpaep, Annelies Vandersteen, Ine Segers-Nolten, Kees Van Der Werf, Vinod Subramaniam, Dries Braeken, Geert Callewaert, Carmen Bartic, Rudi D’Hooge, Ivo Cristiano Martins, Frederic Rousseau*, Joost Schymkowitz* and Bart De Strooper* Department for Molecular and(More)
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(More)
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(More)
The aim of this work is to evaluate the impact of sulfhydryl groups on ovalbumin aggregation and gelation. Ovalbumin was chemically modified to add sulfhydryl groups in various degrees. The rate of aggregation was not affected by the introduction of sulfhydryl groups, and disulfide bond formation was preceded by physical interactions. Hence, disulfide(More)