Abstract

Background

Overactivation of ryanodine receptors and the resulting impaired calcium homeostasis contribute to Alzheimer’s disease–related pathophysiology. This study hypothesized that exposing neuronal progenitors derived from induced pluripotent stems cells of patients with Alzheimer’s disease to dantrolene will increase survival, proliferation, neurogenesis, and synaptogenesis.

Methods

Induced pluripotent stem cells obtained from skin fibroblast of healthy subjects and patients with familial and sporadic Alzheimer’s disease were used. Biochemical and immunohistochemical methods were applied to determine the effects of dantrolene on the viability, proliferation, differentiation, and calcium dynamics of these cells.

Results

Dantrolene promoted cell viability and proliferation in these two cell lines. Compared with the control, differentiation into basal forebrain cholinergic neurons significantly decreased by 10.7% (32.9 ± 3.6% vs. 22.2 ± 2.6%, N = 5, P = 0.004) and 9.2% (32.9 ± 3.6% vs. 23.7 ± 3.1%, N = 5, P = 0.017) in cell lines from sporadic and familial Alzheimer’s patients, respectively, which were abolished by dantrolene. Synapse density was significantly decreased in cortical neurons generated from stem cells of sporadic Alzheimer’s disease by 58.2% (237.0 ± 28.4 vs. 99.0 ± 16.6 arbitrary units, N = 4, P = 0.001) or familial Alzheimer’s disease by 52.3% (237.0 ± 28.4 vs.113.0 ± 34.9 vs. arbitrary units, N = 5, P = 0.001), which was inhibited by dantrolene in the familial cell line. Compared with the control, adenosine triphosphate (30 µM) significantly increased higher peak elevation of cytosolic calcium concentrations in the cell line from sporadic Alzheimer’s patients (84.1 ± 27.0% vs. 140.4 ± 40.2%, N = 5, P = 0.049), which was abolished by the pretreatment of dantrolene. Dantrolene inhibited the decrease of lysosomal vacuolar-type H+-ATPase and the impairment of autophagy activity in these two cell lines from Alzheimer’s disease patients.

Conclusions

Dantrolene ameliorated the impairment of neurogenesis and synaptogenesis, in association with restoring intracellular Ca2+ homeostasis and physiologic autophagy, cell survival, and proliferation in induced pluripotent stem cells and their derived neurons from sporadic and familial Alzheimer’s disease patients.

Editor’s Perspective
What We Already Know about This Topic
  • Overactivation of ryanodine receptors in the endoplasmic reticulum and the resulting dysregulation of calcium homeostasis contribute to Alzheimer’s disease–related pathophysiology

  • Dantrolene is an antagonist of ryanodine receptors, and its chronic use has been suggested to improve memory function in experimental models of Alzheimer’s disease

What This Article Tells Us That Is New
  • Survival, proliferation, and differentiation of neuronal progenitors derived from patients with Alzheimer’s disease are impaired when compared with healthy counterparts

  • Chronic exposure of induced pluripotent stem cells, derived from patients with Alzheimer’s disease, to dantrolene improves the survival, proliferation, and differentiation of these cells

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