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Highly potent intracellular membrane-associated A? seeds.


ABSTRACT: An early event in Alzheimer's disease (AD) pathogenesis is the formation of extracellular aggregates of amyloid-? peptide (A?), thought to be initiated by a prion-like seeding mechanism. However, the molecular nature and location of the A? seeds remain rather elusive. Active A? seeds are found in crude homogenates of amyloid-laden brains and in the soluble fraction thereof. To analyze the seeding activity of the pellet fraction, we have either separated or directly immunoisolated membranes from such homogenates. Here, we found considerable A? seeding activity associated with membranes in the absence of detectable amyloid fibrils. We also found that A? seeds on mitochondrial or associated membranes efficiently induced A? aggregation in vitro and seed ?-amyloidosis in vivo. A? seeds at intracellular membranes may contribute to the spreading of A? aggregation along neuronal pathways and to the induction of intracellular pathologies downstream of A?.

SUBMITTER: Marzesco AM 

PROVIDER: S-EPMC4911570 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Highly potent intracellular membrane-associated Aβ seeds.

Marzesco Anne-Marie AM   Flötenmeyer Matthias M   Bühler Anika A   Obermüller Ulrike U   Staufenbiel Matthias M   Jucker Mathias M   Baumann Frank F  

Scientific reports 20160617


An early event in Alzheimer's disease (AD) pathogenesis is the formation of extracellular aggregates of amyloid-β peptide (Aβ), thought to be initiated by a prion-like seeding mechanism. However, the molecular nature and location of the Aβ seeds remain rather elusive. Active Aβ seeds are found in crude homogenates of amyloid-laden brains and in the soluble fraction thereof. To analyze the seeding activity of the pellet fraction, we have either separated or directly immunoisolated membranes from  ...[more]

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