10 research outputs found
Role of amyloid-β glycine 33 in oligomerization, toxicity, and neuronal plasticity
The aggregation of the amyloid-{beta} (Abeta) peptide plays a pivotal role in the pathogenesis of Alzheimer's disease, as soluble oligomers are intimately linked to neuronal toxicity and inhibition of hippocampal long-term potentiation (LTP). In the C-terminal region of Abeta there are three consecutive GxxxG dimerization motifs, which we could previously demonstrate to play a critical role in the generation of Abeta. Here, we show that glycine 33 (G33) of the central GxxxG interaction motif within the hydrophobic Abeta sequence is important for the aggregation dynamics of the peptide. Abeta peptides with alanine or isoleucine substitutions of G33 displayed an increased propensity to form higher oligomers, which we could attribute to conformational changes. Importantly, the oligomers of G33 variants were much less toxic than Abeta(42) wild type (WT), in vitro and in vivo. Also, whereas Abeta(42) WT is known to inhibit LTP, Abeta(42) G33 variants had lost the potential to inhibit LTP. Our findings reveal that conformational changes induced by G33 substitutions unlink toxicity and oligomerization of Abeta on the molecular level and suggest that G33 is the key amino acid in the toxic activity of Abeta. Thus, a specific toxic conformation of Abeta exists, which represents a promising target for therapeutic interventions
Recommended from our members
Wilcox sandstone reservoirs in the deep subsurface along the Texas Gulf Coast - their potential for production of geopressured geothermal energy. Final report
The following subjects are included: regional setting, stratigraphic sections, Lower Wilcox sandstone distribution, formation pressure, formation temperature used to delineate geothermal fairways, Zapata Fairway, Duval Fairway, Live Oak Fairway, De Witt Fairway, Colorado Fairway, and Harris Fairway. Depositional and structural style, formation pressures and temperatures, porosity and permeability, formation water salinity, and Cuero Prospect are covered for De Witt Fairway. Depositional and structural style, formation and fluid properties, and Eagle Lake Prospect are covered for Colorado Fairway. (MHR
Novel APP/Aβ mutation K16N produces highly toxic heteromeric Aβ oligomers
Here, we describe a novel missense mutation in the amyloid precursor protein (APP) causing a lysine-to-asparagine substitution at position 687 (APP770; herein, referred to as K16N according to amyloid-{beta} (A{beta}) numbering) resulting in an early onset dementia with an autosomal dominant inheritance pattern. The K16N mutation is located exactly at the {alpha}-secretase cleavage site and influences both APP and A{beta}. First, due to the K16N mutation APP secretion is affected and a higher amount of A{beta} peptides is being produced. Second, A{beta} peptides carrying the K16N mutation are unique in that the peptide itself is not harmful to neuronal cells. Severe toxicity, however, is evident upon equimolar mixture of wt and mutant peptides, mimicking the heterozygous state of the subject. Furthermore, A{beta}42 K16N inhibits fibril formation of A{beta}42 wild-type. Even more, A{beta}42 K16N peptides are protected against clearance activity by the major A{beta}-degrading enzyme neprilysin. Thus the mutation characterized here harbours a combination of risk factors that synergistically may contribute to the development of early onset Alzheimer disease