Chronic γ-secretase inhibition reduces amyloid plaque-associated instability of pre- and postsynaptic structures.
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 (APP(swe)/PS1(L166P))-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.
1] Max Planck Institute of Neurobiology, Martinsried, Germany [2] Department of Biochemistry, Adolf-Butenandt-Institute, Ludwig-Maximilians-University, Munich, Germany.
S
S
Liebscher
Department of Biochemistry, Adolf-Butenandt-Institute, Ludwig-Maximilians-University, Munich, Germany.
R M
RM
Page
Max Planck Institute of Neurobiology, Martinsried, Germany.
K
K
Käfer
Department of Biochemistry, Adolf-Butenandt-Institute, Ludwig-Maximilians-University, Munich, Germany.
E
E
Winkler
201;lan Pharmaceuticals, Inc., Cambridge, MA, USA.
K
K
Quinn
201;lan Pharmaceuticals, Inc., Cambridge, MA, USA.
E
E
Goldbach
201;lan Pharmaceuticals, Inc., Cambridge, MA, USA.
E F
EF
Brigham
201;lan Pharmaceuticals, Inc., Cambridge, MA, USA.
D
D
Quincy
201;lan Pharmaceuticals, Inc., Cambridge, MA, USA.
G S
GS
Basi
Prothena Biosciences, South San Francisco, CA, USA.
D B
DB
Schenk
1] Department of Biochemistry, Adolf-Butenandt-Institute, Ludwig-Maximilians-University, Munich, Germany [2] German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
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H
Steiner
Max Planck Institute of Neurobiology, Martinsried, Germany.
T
T
Bonhoeffer
1] Department of Biochemistry, Adolf-Butenandt-Institute, Ludwig-Maximilians-University, Munich, Germany [2] German Center for Neurodegenerative Diseases (DZNE), Munich, Germany [3] Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
C
C
Haass
Department of Biochemistry, Adolf-Butenandt-Institute, Ludwig-Maximilians-University, Munich, Germany.
M
M
Meyer-Luehmann
Max Planck Institute of Neurobiology, Martinsried, Germany.
M
M
Hübener
D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D049229:Dendritic Spines / Q000473:pathology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D036641:Microscopy, Fluorescence, Multiphoton; D058225:Plaque, Amyloid / Q000188:drug therapy* / Q000473:pathology; D053764:Presenilin-1 / Q000235:genetics; D017729:Presynaptic Terminals / Q000473:pathology*; D011804:Quinolines / Q000494:pharmacology* / Q000627:therapeutic use; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use
D016564:Amyloid beta-Protein Precursor; C000597293:ELN594; D004791:Enzyme Inhibitors; D053764:Presenilin-1; D011804:Quinolines; D013449:Sulfonamides; D053829:Amyloid Precursor Protein Secretases