Modifying Rap1-signalling by targeting Pde6δ is neuroprotective in models of Alzheimer’s disease
Abstract Background Neuronal Ca2+ dyshomeostasis and hyperactivity play a central role in Alzheimer’s disease pathology and progression. Amyloid-beta together with non-genetic risk-factors of Alzheimer’s disease contributes to increased Ca2+ influx and aberrant neuronal activity, which accelerates n...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2018-09-01
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| Series: | Molecular Neurodegeneration |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13024-018-0283-3 |
| _version_ | 1818005821633593344 |
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| author | Michael Dumbacher Tom Van Dooren Katrien Princen Koen De Witte Mélissa Farinelli Sam Lievens Jan Tavernier Wim Dehaen Stefaan Wera Joris Winderickx Sara Allasia Amuri Kilonda Stéphane Spieser Arnaud Marchand Patrick Chaltin Casper C. Hoogenraad Gerard Griffioen |
| author_facet | Michael Dumbacher Tom Van Dooren Katrien Princen Koen De Witte Mélissa Farinelli Sam Lievens Jan Tavernier Wim Dehaen Stefaan Wera Joris Winderickx Sara Allasia Amuri Kilonda Stéphane Spieser Arnaud Marchand Patrick Chaltin Casper C. Hoogenraad Gerard Griffioen |
| author_sort | Michael Dumbacher |
| collection | DOAJ |
| description | Abstract Background Neuronal Ca2+ dyshomeostasis and hyperactivity play a central role in Alzheimer’s disease pathology and progression. Amyloid-beta together with non-genetic risk-factors of Alzheimer’s disease contributes to increased Ca2+ influx and aberrant neuronal activity, which accelerates neurodegeneration in a feed-forward fashion. As such, identifying new targets and drugs to modulate excessive Ca2+ signalling and neuronal hyperactivity, without overly suppressing them, has promising therapeutic potential. Methods Here we show, using biochemical, electrophysiological, imaging, and behavioural tools, that pharmacological modulation of Rap1 signalling by inhibiting its interaction with Pde6δ normalises disease associated Ca2+ aberrations and neuronal activity, conferring neuroprotection in models of Alzheimer’s disease. Results The newly identified inhibitors of the Rap1-Pde6δ interaction counteract AD phenotypes, by reconfiguring Rap1 signalling underlying synaptic efficacy, Ca2+ influx, and neuronal repolarisation, without adverse effects in-cellulo or in-vivo. Thus, modulation of Rap1 by Pde6δ accommodates key mechanisms underlying neuronal activity, and therefore represents a promising new drug target for early or late intervention in neurodegenerative disorders. Conclusion Targeting the Pde6δ-Rap1 interaction has promising therapeutic potential for disorders characterised by neuronal hyperactivity, such as Alzheimer’s disease. |
| first_indexed | 2024-04-14T04:50:32Z |
| format | Article |
| id | doaj.art-d568da05c95f4ce298de12d9db169d2b |
| institution | Directory Open Access Journal |
| issn | 1750-1326 |
| language | English |
| last_indexed | 2024-04-14T04:50:32Z |
| publishDate | 2018-09-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Neurodegeneration |
| spelling | doaj.art-d568da05c95f4ce298de12d9db169d2b2022-12-22T02:11:19ZengBMCMolecular Neurodegeneration1750-13262018-09-0113112110.1186/s13024-018-0283-3Modifying Rap1-signalling by targeting Pde6δ is neuroprotective in models of Alzheimer’s diseaseMichael Dumbacher0Tom Van Dooren1Katrien Princen2Koen De Witte3Mélissa Farinelli4Sam Lievens5Jan Tavernier6Wim Dehaen7Stefaan Wera8Joris Winderickx9Sara Allasia10Amuri Kilonda11Stéphane Spieser12Arnaud Marchand13Patrick Chaltin14Casper C. Hoogenraad15Gerard Griffioen16reMYND NVreMYND NVreMYND NVreMYND NVE-Phy-ScienceOrionis BiosciencesCytokine Receptor Lab, Flanders Institute of Biotechnology, Medical Biotechnology Center, Faculty of Medicine and Health Sciences, Ghent UniversityDepartment of Chemistry, KU LeuvenViroVet NVDepartment of Biology, Functional Biology, KU LeuvenCistim Leuven vzwCistim Leuven vzwCistim Leuven vzwCistim Leuven vzwCistim Leuven vzwCell Biology, Department of Biology, Faculty of Science, Utrecht UniversityreMYND NVAbstract Background Neuronal Ca2+ dyshomeostasis and hyperactivity play a central role in Alzheimer’s disease pathology and progression. Amyloid-beta together with non-genetic risk-factors of Alzheimer’s disease contributes to increased Ca2+ influx and aberrant neuronal activity, which accelerates neurodegeneration in a feed-forward fashion. As such, identifying new targets and drugs to modulate excessive Ca2+ signalling and neuronal hyperactivity, without overly suppressing them, has promising therapeutic potential. Methods Here we show, using biochemical, electrophysiological, imaging, and behavioural tools, that pharmacological modulation of Rap1 signalling by inhibiting its interaction with Pde6δ normalises disease associated Ca2+ aberrations and neuronal activity, conferring neuroprotection in models of Alzheimer’s disease. Results The newly identified inhibitors of the Rap1-Pde6δ interaction counteract AD phenotypes, by reconfiguring Rap1 signalling underlying synaptic efficacy, Ca2+ influx, and neuronal repolarisation, without adverse effects in-cellulo or in-vivo. Thus, modulation of Rap1 by Pde6δ accommodates key mechanisms underlying neuronal activity, and therefore represents a promising new drug target for early or late intervention in neurodegenerative disorders. Conclusion Targeting the Pde6δ-Rap1 interaction has promising therapeutic potential for disorders characterised by neuronal hyperactivity, such as Alzheimer’s disease.http://link.springer.com/article/10.1186/s13024-018-0283-3Alzheimer’s diseaseHyperexcitabilityNeuroprotectionPde6δRap1 |
| spellingShingle | Michael Dumbacher Tom Van Dooren Katrien Princen Koen De Witte Mélissa Farinelli Sam Lievens Jan Tavernier Wim Dehaen Stefaan Wera Joris Winderickx Sara Allasia Amuri Kilonda Stéphane Spieser Arnaud Marchand Patrick Chaltin Casper C. Hoogenraad Gerard Griffioen Modifying Rap1-signalling by targeting Pde6δ is neuroprotective in models of Alzheimer’s disease Molecular Neurodegeneration Alzheimer’s disease Hyperexcitability Neuroprotection Pde6δ Rap1 |
| title | Modifying Rap1-signalling by targeting Pde6δ is neuroprotective in models of Alzheimer’s disease |
| title_full | Modifying Rap1-signalling by targeting Pde6δ is neuroprotective in models of Alzheimer’s disease |
| title_fullStr | Modifying Rap1-signalling by targeting Pde6δ is neuroprotective in models of Alzheimer’s disease |
| title_full_unstemmed | Modifying Rap1-signalling by targeting Pde6δ is neuroprotective in models of Alzheimer’s disease |
| title_short | Modifying Rap1-signalling by targeting Pde6δ is neuroprotective in models of Alzheimer’s disease |
| title_sort | modifying rap1 signalling by targeting pde6δ is neuroprotective in models of alzheimer s disease |
| topic | Alzheimer’s disease Hyperexcitability Neuroprotection Pde6δ Rap1 |
| url | http://link.springer.com/article/10.1186/s13024-018-0283-3 |
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