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
