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

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Liebscher,  Sabine
Department: Synapses-Circuits-Plasticity / Bonhoeffer, MPI of Neurobiology, Max Planck Society;

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Bonhoeffer,  Tobias
Department: Synapses-Circuits-Plasticity / Bonhoeffer, MPI of Neurobiology, Max Planck Society;

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Hübener,  M.
Department: Synapses-Circuits-Plasticity / Bonhoeffer, MPI of Neurobiology, Max Planck Society;

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mp2013122a.pdf
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Citation

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.


Cite as: http://hdl.handle.net/11858/00-001M-0000-0015-3DA8-E
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.