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

Abstract

BackgroundNeuronal 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.MethodsHere 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.ResultsThe 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.ConclusionTargeting the Pde6δ-Rap1 interaction has promising therapeutic potential for disorders characterised by neuronal hyperactivity, such as Alzheimer’s disease.Electronic supplementary materialThe online version of this article (10.1186/s13024-018-0283-3) contains supplementary material, which is available to authorized users.

Small GTPases of the Ras and Rho Families Switch on/off Signaling Pathways in Neurodegenerative Diseases

“…Rap1 also controls neuronal activity via ERK. Phosphodiesterase 6δ (PDE6δ) interacts with Rap1 to control MAPK subcellular localization [ 45 ]. Thus, PDE6δ functions as a regulator of Rap1 by regulating the MAPK pools that will activate the GTPase.…”

“…Thus, PDE6δ functions as a regulator of Rap1 by regulating the MAPK pools that will activate the GTPase. PDE6δ also regulates Rap1 recycling from the endomembrane to the plasma membrane [ 45 ]. Blockade of the PDE6δ/Rap1 interaction increases the presence and activity of Rap1 in the endomembrane, favoring the reduction of neuronal activity.…”

Integration of Rap1 and Calcium Signaling

“…PDE6δ (retinal rod rhodopsin-sensitive cGMP 3 ,5 -cyclic phosphodiesterase, subunit delta) interacts with prenylated Rap1 in neurons and interferes with its trafficking, thereby dissociating it from the cell membrane, which is where Rap1 promotes Ca 2+ influx [23]. In this way, the inhibition of Rap1 interaction with PDE6δ has been proven to be beneficial in restraining disease-associated, abnormal Ca 2+ influx and neuronal hyperactivity, and providing neuroprotection in models of Alzheimer's disease [24].…”

“…Interestingly, the modulation of prenylated Rap1 appears to play a role in controlling disease-associated Ca 2+ aberrations and neuronal activity. The inhibition of Rap1 interaction with PDE6δ restrains disease-associated abnormal Ca 2+ influx and neuronal hyperactivity and confers neuroprotection in models of Alzheimer's disease [24]. Rap1 may be an important therapeutic target for the treatment of neuro-degenerative disorders associated with Ca 2+ aberrations, such as Alzheimer's disease.…”

Identification of functionally connected multi-omic biomarkers for Alzheimer’s Disease using modularity-constrained Lasso

“…The impaired 249 insulin-PI3K-Akt signaling observed in the AD brain has led to clinical trials studying 250 whether the enhancement of this pathway using intranasal insulin (IN) treatment is 251 beneficial [44]. Other enriched pathways that are previously reported with a key role in 252 AD include Focal adhesion [45], Ras signaling pathway [46], ECM-receptor interaction [47], 253 MAPK signaling pathway [48], Rap1 signaling pathway [49], etc. In addition, we observe 254 many of the top enriched pathways are related to cancer, such as PI3K -Akt signaling 255 pathway, Prostate cancer and small lung cancer.…”