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

The amyloid precursor protein and its homologues: Structural and functional aspects of native and pathogenic oligomerization.

Over the last 25 years, remarkable progress has been made not only in identifying key molecules of Alzheimer's disease but also in understanding their meaning in the pathogenic state. One hallmark of Alzheimer pathology is the amyloid plaque. A major component of the extracellular deposit is the amyloid-beta (A beta) peptide which is generated from its larger precursor molecule, i.e., the amyloid precursor protein (APP) by consecutive cleavages. Processing is exerted by two enzymes, i.e., the beta-secretase and the gamma-secretase. We and others have found that the self-association of the amyloid peptide and the dimerization and oligomerization of these proteins is a key factor under native and pathogenic conditions. In particular, the A beta homodimer represents a nidus for plaque formation and a well defined therapeutic target. Further, dimerization of the APP was reported to increase generation of toxic A beta whereas heterodimerization with its homologues amyloid precursor like proteins (APLP1 and APLP2) decreased A beta formation. This review mainly focuses on structural features of the homophilic and heterophilic interactions among APP family proteins. The proposed contact sites are described and the consequences of protein dimerization on their functions and in the pathogenesis of Alzheimer's disease are discussed

Considerable doubt about rubella screening and vaccination among unvaccinated orthodox protestant women: a mixed-methods study

BackgroundWomen who are susceptible to rubella are advised to vaccinate against rubella to prevent infection in future pregnancies, and thus avert the risk of congenital rubella syndrome in their unborn child. Rubella outbreaks periodically occur in the under-vaccinated orthodox Protestant community in the Netherlands. The objective of this mixed-methods study was to determine and understand personal experience with rubella, perceived rubella susceptibility, and intention to accept rubella screening and vaccination among unvaccinated orthodox Protestant women. The ultimate aim of this study was to inform policy and practice and contribute to the prevention of cases of congenital rubella syndrome.MethodsA mixed-methods study was conducted combining an online survey and semi-structured interviews among unvaccinated Dutch orthodox Protestant women aged 18-40 years. Descriptive analysis was used for quantitative data. Qualitative data was analysed using codes and categories.ResultsResults of the survey (167 participants) showed that most participants had personal experience with rubella (74%, 123/167) and 101 women (61%, 101/167) indicated they had had rubella themselves. More than half of the women were undecided whether to accept rubella susceptibility screening (56%; 87/156) or rubella vaccination (55%; 80/146). Qualitative findings (10 participants) showed that most women thought they were not susceptible to rubella. Indecisiveness and negative attitudes to accept rubella vaccination were related with religious arguments to object vaccination and with women's perception of absence of imminent threat of rubella. Furthermore, results showed presence of misconceptions among women in the interpretation of their susceptibility and high confidence in their parents' memory that they had experienced rubella as a child although no laboratory screening had been conducted.ConclusionsIn light of an imminent rubella outbreak in the Netherlands, a tailored education campaign should be prepared aimed at and established in cooperation with the under-vaccinated orthodox Protestant community. Health care providers should provide adequate information on rubella and support decision-making in order to stimulate women to make a deliberate and informed decision on rubella screening and, if necessary, subsequent vaccination

Intracellular A? pathology and early cognitive impairments in a transgenic rat overexpressing human amyloid precursor protein: A multidimensional study

10.1186/2051-5960-2-61Acta Neuropathologica Communications216

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

Prevalence, recovery patterns and predictors of quality of life and costs after non-fatal injury: the Brabant Injury Outcome Surveillance (BIOS) study

Item does not contain fulltextINTRODUCTION: Trauma is a major public health problem worldwide that leads to high medical and societal costs. Overall, improved understanding of the full spectrum of the societal impact and burden of injury is needed. The main purpose of the Brabant Injury Outcome Surveillance (BIOS) study is to provide insight into prevalence, predictors and recovery patterns of short-term and long-term health-related quality of life (HRQoL) and costs after injury. MATERIALS AND METHODS: This is a prospective, observational, follow-up cohort study in which HRQoL, psychological, social and functional outcome, and costs after trauma will be assessed during 24 months follow-up within injured patients admitted in 1 of 10 hospitals in the county Noord-Brabant, the Netherlands. Data will be collected by self-reported questionnaires at 1 week (including preinjury assessment), and 1, 3, 6, 12 and 24 months after injury. If patients are not capable of filling out the questionnaires, proxies will be asked to participate. Also, information about mechanism and severity of injury, comorbidity and indirect and direct costs will be collected. Mixed models will be used to examine the course of HRQoL, functional and psychological outcome, costs over time and between different groups, and to identify predictors for poor or good outcome. RELEVANCE: This study should make a substantial contribution to the international collaborative effort to assess the societal impact and burden of injuries more accurately. The BIOS results will also be used to develop an outcome prediction model for outcome evaluation including, besides the classic fatal, non-fatal outcome. TRIAL REGISTRATION NUMBER: NCT02508675