Researchers are exploring whether these ubiquitous fluorinated molecules might worsen infections or hamper vaccine effectiveness.
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Edited by Vincent T. Marchesi, Yale University School of Medicine, New Haven, CT, and approved August 26, 2020 (received for review May 20, 2019)
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.
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.
References
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Clinically approved IVIg delivered to the hippocampus with focused ultrasound promotes neurogenesis in a model of Alzheimer’s disease
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