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Research Article

Clinically approved IVIg delivered to the hippocampus with focused ultrasound promotes neurogenesis in a model of Alzheimer’s disease

Sonam Dubey, View ORCID ProfileStefan Heinen, Slavica Krantic, JoAnne McLaurin, View ORCID ProfileDonald R. Branch, Kullervo Hynynen, and View ORCID ProfileIsabelle Aubert
  1. aBiological Sciences, Hurvitz Brain Sciences Research Program, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, ON M4N 3M5, Canada;
  2. bLaboratory Medicine and Pathobiology, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A1, Canada;
  3. cSorbonne Université, Inserm, Centre de Recherche Saint-Antoine, CRSA, F-75012 Paris, France;
  4. dCentre for Innovation, Canadian Blood Services, Toronto, ON M5G 2M1, Canada;
  5. ePhysical Sciences, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, ON M4N 3M5, Canada;
  6. fMedical Biophysics, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A1, Canada

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PNAS December 22, 2020 117 (51) 32691-32700; first published December 7, 2020; https://doi.org/10.1073/pnas.1908658117
Sonam Dubey
aBiological Sciences, Hurvitz Brain Sciences Research Program, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, ON M4N 3M5, Canada;
bLaboratory Medicine and Pathobiology, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A1, Canada;
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Stefan Heinen
aBiological Sciences, Hurvitz Brain Sciences Research Program, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, ON M4N 3M5, Canada;
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  • ORCID record for Stefan Heinen
Slavica Krantic
cSorbonne Université, Inserm, Centre de Recherche Saint-Antoine, CRSA, F-75012 Paris, France;
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JoAnne McLaurin
aBiological Sciences, Hurvitz Brain Sciences Research Program, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, ON M4N 3M5, Canada;
bLaboratory Medicine and Pathobiology, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A1, Canada;
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Donald R. Branch
dCentre for Innovation, Canadian Blood Services, Toronto, ON M5G 2M1, Canada;
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  • ORCID record for Donald R. Branch
Kullervo Hynynen
ePhysical Sciences, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, ON M4N 3M5, Canada;
fMedical Biophysics, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A1, Canada
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Isabelle Aubert
aBiological Sciences, Hurvitz Brain Sciences Research Program, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, ON M4N 3M5, Canada;
bLaboratory Medicine and Pathobiology, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A1, Canada;
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  • ORCID record for Isabelle Aubert
  • For correspondence: isabelle.aubert@utoronto.ca
  1. Edited by Vincent T. Marchesi, Yale University School of Medicine, New Haven, CT, and approved August 26, 2020 (received for review May 20, 2019)

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Significance

The efficacy of immunotherapy in Alzheimer’s disease is limited, partly because antibodies, administered peripherally, have poor access to the brain. Focused ultrasound (FUS) with microbubbles allows the passage of antibodies from the blood to the brain. In a mouse model of Alzheimer’s disease, antibodies administered in the blood, with and without FUS, reduced amyloid pathology. In contrast, FUS was required to deliver sufficient antibodies to the hippocampus and effectively promote neurogenesis. Neurogenesis, a regenerative process involved in memory functions, is impaired in Alzheimer’s disease. Putative contributors to the stimulation of neurogenesis include a decrease in the proinflammatory cytokine TNF-α. FUS holds potential to increase the efficacy of immunotherapy for Alzheimer’s disease.

Abstract

Preclinical and clinical data support the use of focused ultrasound (FUS), in the presence of intravenously injected microbubbles, to safely and transiently increase the permeability of the blood–brain barrier (BBB). FUS-induced BBB permeability has been shown to enhance the bioavailability of administered intravenous therapeutics to the brain. Ideal therapeutics candidates for this mode of delivery are those capable of inducing benefits peripherally following intravenous injection and in the brain at FUS-targeted areas. In Alzheimer’s disease, intravenous immunoglobulin (IVIg), a fractionated human blood product containing polyclonal antibodies, act as immunomodulator peripherally and centrally, and it can reduce amyloid pathology in the brain. Using the TgCRND8 mouse model of amyloidosis, we tested whether FUS can improve the delivery of IVIg, administered intravenously (0.4 g/kg), to the hippocampus and reach an effective dose to reduce amyloid plaque pathology and promote neurogenesis. Our results show that FUS-induced BBB permeability is required to deliver a significant amount of IVIg (489 ng/mg) to the targeted hippocampus of TgCRN8 mice. Two IVIg-FUS treatments, administered at days 1 and 8, significantly increased hippocampal neurogenesis by 4-, 3-, and 1.5-fold in comparison to saline, IVIg alone, and FUS alone, respectively. Amyloid plaque pathology was significantly reduced in all treatment groups: IVIg alone, FUS alone, and IVIg-FUS. Putative factors promoting neurogenesis in response to IVIg-FUS include the down-regulation of the proinflammatory cytokine TNF-α in the hippocampus. In summary, FUS was required to deliver an effective dose of IVIg to promote hippocampal neurogenesis and modulate the inflammatory milieu.

  • MRI-guided focused ultrasound
  • blood–brain barrier
  • immunotherapy
  • intravenous immunoglobulin
  • neurogenesis

Footnotes

  • ↵1To whom correspondence may be addressed. Email: isabelle.aubert{at}utoronto.ca.
  • Author contributions: S.D., J.M., D.R.B., K.H., and I.A. designed research; S.D. and S.H. performed research; D.R.B. contributed new reagents/analytic tools; S.D. and S.H. analyzed data; and S.D., S.K., and I.A. wrote the paper.

  • The authors declare no competing interest.

  • This article is a PNAS Direct Submission.

  • This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.1908658117/-/DCSupplemental.

Data Availability.

All study data are included in the article and SI Appendix.

Published under the PNAS license.

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Clinically approved IVIg delivered to the hippocampus with focused ultrasound promotes neurogenesis in a model of Alzheimer’s disease
Sonam Dubey, Stefan Heinen, Slavica Krantic, JoAnne McLaurin, Donald R. Branch, Kullervo Hynynen, Isabelle Aubert
Proceedings of the National Academy of Sciences Dec 2020, 117 (51) 32691-32700; DOI: 10.1073/pnas.1908658117

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Clinically approved IVIg delivered to the hippocampus with focused ultrasound promotes neurogenesis in a model of Alzheimer’s disease
Sonam Dubey, Stefan Heinen, Slavica Krantic, JoAnne McLaurin, Donald R. Branch, Kullervo Hynynen, Isabelle Aubert
Proceedings of the National Academy of Sciences Dec 2020, 117 (51) 32691-32700; DOI: 10.1073/pnas.1908658117
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Proceedings of the National Academy of Sciences: 117 (51)
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