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  Chronic γ-secretase inhibition reduces amyloid plaque-associated instability of pre- and postsynaptic structures

Liebscher, S., Page, R. M., Käfer, K., Winkler, E., Quinn, K., Goldbach, E., et al. (2014). Chronic γ-secretase inhibition reduces amyloid plaque-associated instability of pre- and postsynaptic structures. Molecular Psychiatry, 19(8), 937-946. doi:10.1038/mp.2013.122.

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Liebscher, Sabine1, Author              
Page, R. M., Author
Käfer, K, Author
Winkler, E, Author
Quinn, K, Author
Goldbach, E, Author
Brigham, E. F., Author
Quincy, D, Author
Basi, G. S., Author
Schenk, D. B., Author
Steiner, H, Author
Bonhoeffer, Tobias1, Author              
Haass, C, Author
Meyer-Luehmann, M, Author
Hübener, M.1, Author              
Affiliations:
1Department: Synapses-Circuits-Plasticity / Bonhoeffer, MPI of Neurobiology, Max Planck Society, ou_1113545              

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Free keywords: Alzheimer’s disease; APP-transgenic mice; gamma secretase inhibitor; two-photon imaging; dendritic spines; axonal boutons
 Abstract: The loss of synapses is a strong histological correlate of the cognitive decline in Alzheimer’s disease (AD). Amyloid bpeptide (Ab), a cleavage product of the amyloid precursor protein (APP), exerts detrimental effects on synapses, a process thought to be causally related to the cognitive deficits in AD. Here, we used in vivo two-photon microscopy to characterize the dynamics of axonal boutons and dendritic spines in APP/Presenilin 1 (APPswe/PS1L166P)–green fluorescent protein (GFP) transgenic mice. Time-lapse imaging over 4 weeks revealed a pronounced, concerted instability of pre- and postsynaptic structures within the vicinity of amyloid plaques. Treatment with a novel sulfonamide-type g-secretase inhibitor (GSI) attenuated the formation and growth of new plaques and, most importantly, led to a normalization of the enhanced dynamics of synaptic structures close to plaques. GSI treatment did neither affect spines and boutons distant from plaques in amyloid precursor protein/presenilin 1-GFP (APPPS1-GFP) nor those in GFP-control mice, suggesting no obvious neuropathological side effects of the drug.

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Language(s): eng - English
 Dates: 20132014-08
 Publication Status: Published in print
 Pages: 10
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.1038/mp.2013.122
 Degree: -

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Title: Molecular Psychiatry
Source Genre: Journal
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Publ. Info: Houndmills, Hampshire, UK : Stockton Press
Pages: - Volume / Issue: 19 (8) Sequence Number: - Start / End Page: 937 - 946 Identifier: ISSN: 1359-4184
CoNE: https://pure.mpg.de/cone/journals/resource/954925619131