Newly Published
Perioperative Medicine  |   March 2020
Dantrolene Ameliorates Impaired Neurogenesis and Synaptogenesis in Induced Pluripotent Stem Cell Lines Derived from Patients with Alzheimer’s Disease
Author Notes
  • From the Department of Anesthesiology and Critical Care, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania (Y.W., G.L., S.L., Y.S., H.W.); the Department of Anesthesiology, First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China (Y.W.); the Department of Anesthesiology, the First Affiliated Hospital of Jinan University, Guangzhou, China (S.L.); the College of Art and Science, University of Pennsylvania, Philadelphia, Pennsylvania (R.M.); and the Department of Anesthesiology, Children’s Hospital of Fudan University, Shanghai, China (Y.S.).
  • Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided in the HTML text of this article on the Journal’s Web site (www.anesthesiology.org).
    Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided in the HTML text of this article on the Journal’s Web site (www.anesthesiology.org).×
  • Submitted for publication October 6, 2018. Accepted for publication February 3, 2020.
    Submitted for publication October 6, 2018. Accepted for publication February 3, 2020.×
  • Correspondence: Address correspondence to Dr. Wei: University of Pennsylvania, 305 John Morgan Building, 3610 Hamilton Walk, Philadelphia, Pennsylvania 19104. weih@uphs.upenn.edu. Information on purchasing reprints may be found at www.anesthesiology.org or on the masthead page at the beginning of this issue. Anesthesiology’s articles are made freely accessible to all readers, for personal use only, 6 months from the cover date of the issue.
Article Information
Perioperative Medicine / Central and Peripheral Nervous Systems / Geriatric Anesthesia / Pharmacology
Perioperative Medicine   |   March 2020
Dantrolene Ameliorates Impaired Neurogenesis and Synaptogenesis in Induced Pluripotent Stem Cell Lines Derived from Patients with Alzheimer’s Disease
Anesthesiology Newly Published on March 4, 2020. doi:https://doi.org/10.1097/ALN.0000000000003224
Anesthesiology Newly Published on March 4, 2020. doi:https://doi.org/10.1097/ALN.0000000000003224
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