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

Liebscher, Sabine; Page, RM; Käfer, K; Winkler, E; Quinn, K; Goldbach, E; Brigham, EF; Quincy, D; Basi, GS; Schenk, DB; Steiner, H; Bonhoeffer, T; Haass, C; Meyer-Luehmann, M; Hübener, M.

doi:10.1038/mp.2013.122

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Chronic y-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, T
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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Citation

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

Cite as: https://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.