Pharmacological modulation of septins restores calcium homeostasis and is neuroprotective in models of Alzheimer's disease

Science. 2024 May 31;384(6699):eadd6260. doi: 10.1126/science.add6260. Epub 2024 May 31.

Abstract

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-β and tau-driven mouse models of disease, ReS19-T agents restored synaptic plasticity, normalized brain network activity, and attenuated the development of both amyloid-β and tau pathology. Our findings identify the septin cytoskeleton as a potential therapeutic target for the development of disease-modifying AD treatments.

MeSH terms

  • Alzheimer Disease* / drug therapy
  • Alzheimer Disease* / metabolism
  • Amyloid beta-Peptides* / metabolism
  • Animals
  • Calcium Channels / metabolism
  • Calcium Signaling / drug effects
  • Calcium* / metabolism
  • Cytoskeleton / drug effects
  • Cytoskeleton / metabolism
  • Disease Models, Animal
  • Homeostasis*
  • Humans
  • Mice
  • Neuronal Plasticity / drug effects
  • Neuroprotective Agents* / pharmacology
  • Neuroprotective Agents* / therapeutic use
  • Septins* / metabolism
  • tau Proteins* / metabolism

Substances

  • Amyloid beta-Peptides
  • Calcium
  • Calcium Channels
  • Neuroprotective Agents
  • Septins
  • tau Proteins