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

Mol Psychiatry. 2013 Sep 24. doi: 10.1038/mp.2013.122. [Epub ahead of print]

Authors/Editors: Liebscher S, 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.
Publication Date: 2013

Liebscher_2013

Abstract

The loss of synapses is a strong histological correlate of the cognitive decline in Alzheimer's disease (AD). Amyloid β-peptide (Aβ), 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 γ-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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