Gamma-secretase inhibition reduces spine density in vivo via an amyloid precursor protein-dependent pathway
| Autor: | Steffen Burgold, Tobias Bittner, Harald Steiner, Gerda Mitteregger, Christian Haass, Christiane Volbracht, Hans A. Kretzschmar, Christian K.E. Jung, Jochen Herms, Martin Fuhrmann |
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| Rok vydání: | 2009 |
| Předmět: |
Male
Dendritic spine genetics [Alzheimer Disease] Peptide antagonists & inhibitors [Amyloid Precursor Protein Secretases] Synapse pathology [Alzheimer Disease] Amyloid beta-Protein Precursor Mice 0302 clinical medicine Amyloid precursor protein chemistry.chemical_classification Mice Knockout 0303 health sciences biology General Neuroscience P3 peptide Dipeptides deficiency [Amyloid beta-Protein Precursor] 3. Good health Cell biology medicine.anatomical_structure genetics [Amyloid beta-Protein Precursor] Cerebral cortex Female Brief Communications pharmacology [Dipeptides] Signal Transduction drug effects [Signal Transduction] Dendritic Spines physiology [Amyloid beta-Protein Precursor] Mice Transgenic genetics [Signal Transduction] 03 medical and health sciences In vivo Alzheimer Disease medicine Animals enzymology [Dendritic Spines] ddc:610 drug effects [Dendritic Spines] Gamma secretase N-(N-(3 5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester 030304 developmental biology enzymology [Alzheimer Disease] metabolism [Amyloid Precursor Protein Secretases] chemistry biology.protein Amyloid Precursor Protein Secretases pathology [Dendritic Spines] Neuroscience 030217 neurology & neurosurgery |
| Zdroj: | Journal of Neuroscience; Vol 29 The journal of neuroscience 29(33), 10405-10409 (2009). doi:10.1523/JNEUROSCI.2288-09.2009 |
| ISSN: | 1529-2401 |
| DOI: | 10.1523/JNEUROSCI.2288-09.2009 |
| Popis: | Alzheimer's disease (AD) represents the most common age-related neurodegenerative disorder. It is characterized by the invariant accumulation of the β-amyloid peptide (Aβ), which mediates synapse loss and cognitive impairment in AD. Current therapeutic approaches concentrate on reducing Aβ levels and amyloid plaque load via modifying or inhibiting the generation of Aβ. Based onin vivotwo-photon imaging, we present evidence that side effects on the level of dendritic spines may counteract the beneficial potential of these approaches. Two potent γ-secretase inhibitors (GSIs), DAPT (N-[N-(3,5-difluorophenacetyl-l-alanyl)]-S-phenylglycinet-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 γ-secretase inhibition decreases dendritic spine density via APP. Independent of the effects of γ-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 timein vivo. |
| Databáze: | OpenAIRE |
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