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J Neurosci. 2013 Dec 4;33(49):19284-94. doi: 10.1523/JNEUROSCI.2542-13.2013.

Membrane-anchored Aβ accelerates amyloid formation and exacerbates amyloid-associated toxicity in mice.

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Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, D-72076 Tübingen, Germany, Graduate School for Cellular and Molecular Neuroscience, University of Tübingen, D-72076 Tübingen, Germany, German Center for Neurodegenerative Diseases, D-72076 Tübingen, Germany, and Animal Health and Veterinary Laboratories Agency, Lasswade Laboratory, Penicuik EH26 0PZ, Midlothian, United Kingdom.


Pathological, genetic, and biochemical hallmarks of Alzheimer's disease (AD) are linked to amyloid-β (Aβ) peptide aggregation. Especially misfolded Aβ42 peptide is sufficient to promote amyloid plaque formation. However, the cellular compartment facilitating the conversion of monomeric Aβ to aggregated toxic Aβ species remains unknown. In vitro models suggest lipid membranes to be the driving force of Aβ conversion. To this end, we generated two novel mouse models, expressing either membrane-anchored or nonanchored versions of the human Aβ42 peptide. Strikingly, membrane-anchored Aβ42 robustly accelerated Aβ deposition and exacerbated amyloid-associated toxicity upon crossing with Aβ precursor protein transgenic mice. These in vivo findings support the hypothesis that Aβ-membrane interactions play a pivotal role in early-onset AD as well as neuronal damage and provide evidence to study Aβ-membrane interactions as therapeutic targets.


Alzheimer's disease; amyloid formation; membrane anchoring; mouse model; toxicity

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