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Published on: October 17, 2015
Highly potent intracellular membrane-associated Aβ seeds
Anne-Marie Marzesco1,2, Matthias Flötenmeyer3, Anika Bühler1,2
1Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, D-72076 Tübingen, Germany.
Abstract:
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 such homogenates. Here, we found considerable Aβ seeding activity associated with membranes in the absence of detectable amyloid fibrils. We also found that Aβ seeds on mitochondrial or associated membranes efficiently induced Aβ aggregation in vitro and seed β-amyloidosis in vivo. Aβ seeds at intracellular membranes may contribute to the spreading of Aβ aggregation along neuronal pathways and to the induction of intracellular pathologies downstream of Aβ.
Insights
Alzheimer's disease amyloid-beta seeds are found on membranes, not just fibrils. These membrane-bound seeds drive aggregation and disease progression, offering new therapeutic targets.
Area of Science:
- Neuroscience
- Biochemistry
- Pathology
Background:
- Alzheimer's disease (AD) pathogenesis involves amyloid-beta (Aβ) peptide aggregation.
- Prion-like seeding is a proposed mechanism for Aβ aggregate formation.
- The precise molecular nature and location of Aβ seeds remain unclear.
Purpose of the Study:
- To investigate the presence and role of Aβ seeds in membrane fractions.
- To determine if membrane-associated Aβ seeds can initiate and propagate aggregation.
- To explore the implications of intracellular Aβ seeds in AD.
Main Methods:
- Separation and immunoisolation of membrane fractions from amyloid-laden brain homogenates.
- Assay of Aβ seeding activity in membrane fractions.
- In vitro and in vivo studies to assess the aggregation-inducing capacity of membrane-associated seeds.
Main Results:
- Significant Aβ seeding activity was detected in membrane fractions, independent of detectable amyloid fibrils.
- Aβ seeds associated with mitochondrial or related membranes effectively induced Aβ aggregation in vitro.
- These membrane-bound seeds were capable of initiating β-amyloidosis in vivo.
Conclusions:
- Membrane-associated Aβ seeds are a key component in early Alzheimer's disease pathogenesis.
- Intracellular membrane-bound Aβ seeds may facilitate the spread of aggregation and downstream pathologies.
- Targeting these membrane-associated seeds could offer novel therapeutic strategies for Alzheimer's disease.
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