Abnormal calcium signaling is a central pathological component of Alzheimer's disease (AD). Here, we describe the identification of a class of compounds called ReS19-T, which are able to restore calcium homeostasis in cell-based models of tau pathology. Aberrant tau accumulation leads to uncontrolled activation of store-operated calcium channels (SOCCs) by remodeling septin filaments at the cell cortex. Binding of ReS19-T to septins restores filament assembly in the disease state and restrains calcium entry through SOCCs. In amyloid-ß and tau-driven mouse models of disease, ReS19-T agents restored synaptic plasticity, normalized brain network activity, and attenuated the development of both amyloid-ß and tau pathology. Our findings identify the septin cytoskeleton as a potential therapeutic target for the development of disease-modifying AD treatments.
Alzheimer Disease , Amyloid beta-Peptides , Calcium , Homeostasis , Neuroprotective Agents , Septins , tau Proteins , Animals , Humans , Mice , Alzheimer Disease/drug therapy , Alzheimer Disease/metabolism , Amyloid beta-Peptides/metabolism , Calcium/metabolism , Calcium Channels/metabolism , Calcium Signaling/drug effects , Cytoskeleton/metabolism , Cytoskeleton/drug effects , Disease Models, Animal , Neuronal Plasticity/drug effects , Neuroprotective Agents/pharmacology , Neuroprotective Agents/therapeutic use , Septins/metabolism , tau Proteins/metabolism
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.
Alzheimer Disease/metabolism , Cyclic Nucleotide Phosphodiesterases, Type 6/metabolism , Telomere-Binding Proteins/metabolism , rap1 GTP-Binding Proteins/metabolism , Alzheimer Disease/pathology , Amyloid beta-Peptides/metabolism , Animals , Disease Models, Animal , Humans , Mice, Transgenic , Neurons/metabolism , Neurons/pathology , Neuroprotection/physiology , Neuroprotective Agents/therapeutic use , Shelterin Complex , Signal Transduction/physiology
