Linked Life Data

21156804

Source:http://linkedlifedata.com/resource/pubmed/id/21156804

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
10
pubmed:dateCreated
2011-3-10
pubmed:abstractText
The identification of toxic A? species and/or the process of their formation is crucial for understanding the mechanism(s) of A? neurotoxicity in Alzheimer disease and also for the development of effective diagnostic and therapeutic interventions. To elucidate the structural basis of A? toxicity, we developed different procedures to isolate A? species of defined size and morphology distribution, and we investigated their toxicity in different cell lines and primary neurons. We observed that crude A?42 preparations, containing a monomeric and heterogeneous mixture of A?42 oligomers, were more toxic than purified monomeric, protofibrillar fractions, or fibrils. The toxicity of protofibrils was directly linked to their interactions with monomeric A?42 and strongly dependent on their ability to convert into amyloid fibrils. Subfractionation of protofibrils diminished their fibrillization and toxicity, whereas reintroduction of monomeric A?42 into purified protofibril fractions restored amyloid formation and enhanced their toxicity. Selective removal of monomeric A?42 from these preparations, using insulin-degrading enzyme, reversed the toxicity of A?42 protofibrils. Together, our findings demonstrate that A?42 toxicity is not linked to specific prefibrillar aggregate(s) but rather to the ability of these species to grow and undergo fibril formation, which depends on the presence of monomeric A?42. These findings contribute significantly to the understanding of amyloid formation and toxicity in Alzheimer disease, provide novel insight into mechanisms of A? protofibril toxicity, and important implications for designing anti-amyloid therapies.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Mar
pubmed:issn
1083-351X
pubmed:author
pubmed:issnType
Electronic
pubmed:day
11
pubmed:volume
286
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
8585-96
pubmed:meshHeading
pubmed:year
2011
pubmed:articleTitle
Abeta42 neurotoxicity is mediated by ongoing nucleated polymerization process rather than by discrete Abeta42 species.
pubmed:affiliation
Laboratory of Molecular Neurobiology and Neuroproteomics, Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't