Publication: Modifying Rap1-signalling by targeting Pde6δ is neuroprotective in models of Alzheimer's disease.

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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+ signaling and neuronal hyperactivity, without overly suppressing them, has promising therapeutic potential.Here we show, using biochemical, electrophysiological, imaging, and behavioral tools, that pharmacological modulation of Rap1 signaling by inhibiting its interaction with Pde6δ normalizes disease associated Ca2+ aberrations and neuronal activity, conferring neuroprotection in models of Alzheimer's disease.The newly identified inhibitors of the Rap1-Pde6δ interaction counteracts AD phenotypes, by reconfiguring Rap1 signaling underlying synaptic efficacy, Ca2+ influx, and neuronal repolarization, 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. Targeting the Pde6δ-Rap1 interaction has promising therapeutic potential for disorders characterized by neuronal hyperactivity, such as Alzheimer's disease.