Amyloid-β(1-42) aggregation initiates its cellular uptake and cytotoxicity

The accumulation of amyloid beta peptide(1-42) (Abeta(1-42)) in extracellular plaques is one of the pathological hallmarks of Alzheimer disease (AD). Several studies have suggested that cellular reuptake of Abeta(1-42) may be a crucial step in its cytotoxicity, but the uptake mechanism is not yet understood. Abeta may be present in an aggregated form prior to cellular uptake. Alternatively, monomeric peptide may enter the endocytic pathway and conditions in the endocytic compartments may induce the aggregation process. Our study aims to answer the question whether aggregate formation is a prerequisite or a consequence of Abeta endocytosis. We visualized aggregate formation of fluorescently labeled Abeta(1-42) and tracked its internalization by human neuroblastoma cells and neurons. beta-Sheet-rich Abeta(1-42) aggregates entered the cells at low nanomolar concentration of Abeta(1-42). In contrast, monomer uptake faced a concentration threshold and occurred only at concentrations and time scales that allowed Abeta(1-42) aggregates to form. By uncoupling membrane binding from internalization, we found that Abeta(1-42) monomers bound rapidly to the plasma membrane and formed aggregates there. These structures were subsequently taken up and accumulated in endocytic vesicles. This process correlated with metabolic inhibition. Our data therefore imply that the formation of beta-sheet-rich aggregates is a prerequisite for Abeta(1-42) uptake and cytotoxicity

Amyloid-β(1-42) Aggregation Initiates Its Cellular Uptake and Cytotoxicity

The accumulation of amyloid β peptide(1-42) (Aβ(1-42)) in extracellular plaques is one of the pathological hallmarks of Alzheimer disease (AD). Several studies have suggested that cellular reuptake of Aβ(1-42) may be a crucial step in its cytotoxicity, but the uptake mechanism is not yet understood. Aβ may be present in an aggregated form prior to cellular uptake. Alternatively, monomeric peptide may enter the endocytic pathway and conditions in the endocytic compartments may induce the aggregation process. Our study aims to answer the question whether aggregate formation is a prerequisite or a consequence of Aβ endocytosis. We visualized aggregate formation of fluorescently labeled Aβ(1-42) and tracked its internalization by human neuroblastoma cells and neurons. β-Sheet-rich Aβ(1-42) aggregates entered the cells at low nanomolar concentration of Aβ(1-42). In contrast, monomer uptake faced a concentration threshold and occurred only at concentrations and time scales that allowed Aβ(1-42) aggregates to form. By uncoupling membrane binding from internalization, we found that Aβ(1-42) monomers bound rapidly to the plasma membrane and formed aggregates there. These structures were subsequently taken up and accumulated in endocytic vesicles. This process correlated with metabolic inhibition. Our data therefore imply that the formation of β-sheet-rich aggregates is a prerequisite for Aβ(1-42) uptake and cytotoxicity

Amyloid-β(1-42) Aggregation Initiates Its Cellular Uptake and Cytotoxicity

The accumulation of amyloid β peptide(1-42) (Aβ(1-42)) in extracellular plaques is one of the pathological hallmarks of Alzheimer disease (AD). Several studies have suggested that cellular reuptake of Aβ(1-42) may be a crucial step in its cytotoxicity, but the uptake mechanism is not yet understood. Aβ may be present in an aggregated form prior to cellular uptake. Alternatively, monomeric peptide may enter the endocytic pathway and conditions in the endocytic compartments may induce the aggregation process. Our study aims to answer the question whether aggregate formation is a prerequisite or a consequence of Aβ endocytosis. We visualized aggregate formation of fluorescently labeled Aβ(1-42) and tracked its internalization by human neuroblastoma cells and neurons. β-Sheet-rich Aβ(1-42) aggregates entered the cells at low nanomolar concentration of Aβ(1-42). In contrast, monomer uptake faced a concentration threshold and occurred only at concentrations and time scales that allowed Aβ(1-42) aggregates to form. By uncoupling membrane binding from internalization, we found that Aβ(1-42) monomers bound rapidly to the plasma membrane and formed aggregates there. These structures were subsequently taken up and accumulated in endocytic vesicles. This process correlated with metabolic inhibition. Our data therefore imply that the formation of β-sheet-rich aggregates is a prerequisite for Aβ(1-42) uptake and cytotoxicity

Bulgarian sport policy 1945-1989: A strategic relation perspective

The 2008 Beijing Olympic Games have stimulated discussions about the success of different sport systems and the Chinese model in particular. Revisiting explanations of sport in the former communist countries of Eastern Europe during the Cold War seems timely, as the current Chinese model of sport was largely designed after the Soviet example established in this period. This paper examines Bulgarian sport policy between 1945 and 1989. It employs a Strategic Relation approach (Jessop, 1990) to analyse sport policy making as a strategic relation closely linked to the dominant state project of building a new stateness. It goes beyond ideological interpretations and argues that the state represents a strategic terrain where these relations have to be established in struggles, the outcomes of which are always uncertain. Furthermore, past and present struggles and their outcomes create various socio-political environments that presuppose the forms of state selectivity and intervention in sport. The process of constructing sport policy was influenced by two main categories of strategic relations: intra-state, including political, organisational and personal relations between the Party, state apparatus and various sport and non-sport organisations and their managers, and transnational, concerning ideological, political, economic and organisational relations with both communist and western countries and international sport organisations

Synchrony and diachrony of the Bulgarian predicative possessive constructions

The paper investigates the system of predicative possession in Bulgarian from a Slavic and Balkan perspective. The constructions are described in terms of their semantic and syntactic properties and several generalizations are made about the distribution of possessive features such as alienable vs inalienable and permanent vs temporary. In the second part of paper, I bring forward some observations about the diachrony of the Bulgarian predicative possessive constructions and their potential (Slavic or Balkan) source