α-Sheet secondary structure in amyloid ß-peptide drives aggregation and toxicity in Alzheimer's disease.

Alzheimer's disease (AD) is characterized by the deposition of ß-sheet-rich, insoluble amyloid ß-peptide (Aß) plaques; however, plaque burden is not correlated with cognitive impairment in AD patients; instead, it is correlated with the presence of toxic soluble oligomers. Here, we show, by a variety of different techniques, that these Aß oligomers adopt a nonstandard secondary structure, termed "α-sheet." These oligomers form in the lag phase of aggregation, when Aß-associated cytotoxicity peaks, en route to forming nontoxic ß-sheet fibrils. De novo-designed α-sheet peptides specifically and tightly bind the toxic oligomers over monomeric and fibrillar forms of Aß, leading to inhibition of aggregation in vitro and neurotoxicity in neuroblastoma cells. Based on this specific binding, a soluble oligomer-binding assay (SOBA) was developed as an indirect probe of α-sheet content. Combined SOBA and toxicity experiments demonstrate a strong correlation between α-sheet content and toxicity. The designed α-sheet peptides are also active in vivo where they inhibit Aß-induced paralysis in a transgenic Aß Caenorhabditis elegans model and specifically target and clear soluble, toxic oligomers in a transgenic APPsw mouse model. The α-sheet hypothesis has profound implications for further understanding the mechanism behind AD pathogenesis.

Social Exclusion and Parental Incarceration Impacts on Adolescents' Networks and School Engagement.

Although prior research links parental incarceration to deleterious outcomes for children over the life-course, few studies have examined whether such incarceration affects the social exclusion of children during adolescence. Drawing on several lines of scholarship, we examine whether adolescents with incarcerated parents have fewer or lower quality relationships, participate in more antisocial peer networks, and feel less integrated or engaged in school. The study applies propensity score matching to survey and network data from a national sample of youth. Analyses indicated that children with incarcerated parents have more antisocial peers; we found limited evidence, though, that parental incarceration adversely impacts peer networks and school integration domains. Generally, the results suggested that the impacts of parental incarceration on adolescents' social lives have less to do with isolation than with the types of peers adolescents befriend. Findings provide support for the idea that parental incarceration may adversely affect children's social exclusion.