title: Gamma-secretase inhibition reduces spine density in vivo via an amyloid precursor protein-dependent pathway.
abstract: Alzheimer's disease (AD) represents the most common age-related neurodegenerative disorder. It is characterized by the invariant accumulation of the beta-amyloid peptide (Abeta), which mediates synapse loss and cognitive impairment in AD. Current therapeutic approaches concentrate on reducing Abeta levels and amyloid plaque load via modifying or inhibiting the generation of Abeta. Based on in vivo two-photon imaging, we present evidence that side effects on the level of dendritic spines may counteract the beneficial potential of these approaches. Two potent gamma-secretase inhibitors (GSIs), DAPT (N-[N-(3,5-difluorophenacetyl-L-alanyl)]-S-phenylglycine t-butyl ester) and LY450139 (hydroxylvaleryl monobenzocaprolactam), were found to reduce the density of dendritic spines in wild-type mice. In mice deficient for the amyloid precursor protein (APP), both GSIs had no effect on dendritic spine density, demonstrating that gamma-secretase inhibition decreases dendritic spine density via APP. Independent of the effects of gamma-secretase inhibition, we observed a twofold higher density of dendritic spines in the cerebral cortex of adult APP-deficient mice. This observation further supports the notion that APP is involved in the modulation of dendritic spine density--shown here for the first time in vivo.
authors.affiliation: Center of Neuropathology and Prion Research, Ludwig-Maximilians-Universität, Munich, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Bittner
authors.forename: Martin
authors.initials: M
authors.lastname: Fuhrmann
authors.forename: Steffen
authors.initials: S
authors.lastname: Burgold
authors.forename: Christian K E
authors.initials: CK
authors.lastname: Jung
authors.forename: Christiane
authors.initials: C
authors.lastname: Volbracht
authors.forename: Harald
authors.initials: H
authors.lastname: Steiner
authors.forename: Gerda
authors.initials: G
authors.lastname: Mitteregger
authors.forename: Hans A
authors.initials: HA
authors.lastname: Kretzschmar
authors.forename: Christian
authors.initials: C
authors.lastname: Haass
authors.forename: Jochen
authors.initials: J
authors.lastname: Herms
mesh_terms: D000544:Alzheimer Disease / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000818:Animals; D049229:Dendritic Spines / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology*; D004151:Dipeptides / Q000494:pharmacology; D005260:Female; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
chemical_list: D016564:Amyloid beta-Protein Precursor; D004151:Dipeptides; C419410:N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester; D053829:Amyloid Precursor Protein Secretases
references.citation: Neural Comput. 2002 Jun;14(6):1283-310
references.pmid: 12020447
references.citation: J Neuropathol Exp Neurol. 1994 Sep;53(5):438-47
references.pmid: 8083687
references.citation: Neuron. 2004 Apr 8;42(1):23-36
references.pmid: 15066262
references.citation: Arch Neurol. 2008 Aug;65(8):1031-8
references.pmid: 18695053
references.citation: J Pharmacol Exp Ther. 2003 Jun;305(3):864-71
references.pmid: 12626636
references.citation: J Neurosci. 2005 Aug 3;25(31):7278-87
references.pmid: 16079410
references.citation: J Neurosci. 2006 Jul 5;26(27):7212-21
references.pmid: 16822978
references.citation: EMBO Rep. 2002 Jul;3(7):688-94
references.pmid: 12101103
references.citation: J Neurochem. 2001 Jan;76(1):173-81
references.pmid: 11145990
references.citation: J Neurosci. 2007 Jun 6;27(23):6224-33
references.pmid: 17553995
references.citation: Nature. 2006 Jun 22;441(7096):979-83
references.pmid: 16791195
references.citation: Neuron. 2005 Jan 20;45(2):279-91
references.pmid: 15664179
references.citation: Neuron. 2006 Dec 7;52(5):831-43
references.pmid: 17145504
references.citation: Ann Neurol. 1991 Oct;30(4):572-80
references.pmid: 1789684
references.citation: Cell. 2007 Oct 19;131(2):215-21
references.pmid: 17956719
references.citation: Science. 2002 Oct 25;298(5594):789-91
references.pmid: 12399581
references.citation: Nat Neurosci. 2006 Sep;9(9):1117-24
references.pmid: 16892056
references.citation: Nature. 2002 Dec 19-26;420(6917):812-6
references.pmid: 12490949
references.citation: EMBO J. 2004 Feb 11;23(3):483-8
references.pmid: 14749724
references.citation: Nat Neurosci. 2004 Nov;7(11):1181-3
references.pmid: 15475950
references.citation: Neuron. 2003 Mar 27;37(6):925-37
references.pmid: 12670422
references.citation: Nature. 2002 Dec 19-26;420(6917):788-94
references.pmid: 12490942
references.citation: Nature. 2005 Jul 14;436(7048):261-5
references.pmid: 16015331
references.citation: J Neurosci. 2005 Sep 28;25(39):8898-902
references.pmid: 16192379
references.citation: Proc Natl Acad Sci U S A. 1996 Jun 11;93(12):6158-62
references.pmid: 8650236
references.citation: Neuron. 2000 Oct;28(1):41-51
references.pmid: 11086982
references.citation: J Neurosci. 2006 Mar 15;26(11):3021-9
references.pmid: 16540580
references.citation: Nat Rev Mol Cell Biol. 2004 Jun;5(6):499-504
references.pmid: 15173829