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Molecular Neurodegeneration
Published in: Molecular Neurodegeneration 1/2018

Open Access 01-12-2018 | Research article

Modifying Rap1-signalling by targeting Pde6δ is neuroprotective in models of Alzheimer’s disease

Authors: 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

Published in: Molecular Neurodegeneration | Issue 1/2018

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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.
Appendix
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Metadata
Title
Modifying Rap1-signalling by targeting Pde6δ is neuroprotective in models of Alzheimer’s disease
Authors
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
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Molecular Neurodegeneration / Issue 1/2018
Electronic ISSN: 1750-1326
DOI
https://doi.org/10.1186/s13024-018-0283-3

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