Investigating the efficacy of a combination Aβ-targeted treatment in a mouse model of Alzheimer's disease

Mingzhe Liu, Stefan Jevtic, Kelly Markham-Coultes, Nicholas P.K. Ellens, Meaghan A. O'Reilly, Kullervo Hynynen, Isabelle Aubert, Jo Anne McLaurin

Research output: Research - peer-reviewArticle

Abstract

Amyloid-beta peptide (Aβ) plays a critical role in the pathogenesis of Alzheimer's disease (AD). Here, we explored the use of a combination treatment to reduce amyloid load through microglial phagocytosis in a mouse model of AD. We hypothesized that using an initial treatment of magnetic resonance image guided focused ultrasound (MRIgFUS) to transiently increase the blood–brain barrier (BBB) permeability and enhance the delivery of an Aβ-antibody (BAM-10), followed by scyllo-inositol treatment would result in accelerated clearance. TgCRND8 mice expressing both Swedish (KM670/671NL) and Indiana (V717F) APP mutations under the hamster prion (PrP) promoter at 5 months of age were either treated with scyllo-inositol or received an initial MRIgFUS treatment delivering BAM-10 prior to scyllo-inositol treatment for one month. Treated animals and untreated TgCRND8 littermates were then sacrificed at 6 months of age, and their brains were processed for immunohistochemistry and immunofluorescence. Amyloid load was quantified and analyzed through immunohistochemical staining. Astrocyte and microglial activation were quantified and analyzed through immunofluorescent staining. We found that both the scyllo-inositol treatment and combination treatment, MRIgFUS/BAM10+scyllo-inositol, significantly reduced amyloid load and astrocyte activation in the hippocampus and the cortex. Furthermore, in both treatment paradigms microglial activation and phagocytosis was increased in comparison to the untreated mice. There were no differences detected between the two treatment paradigms. We propose that the 30-day scyllo-inositol treatment saturated the early benefit of the MRIgFUS/BAM-10 treatment. In the future, multiple FUS treatments combined with BAM-10 throughout the duration of scyllo-inositol treatment may lead to more effective amyloid clearance.

LanguageEnglish (US)
Pages138-145
Number of pages8
JournalBrain Research
Volume1678
DOIs
StatePublished - Jan 1 2018

Fingerprint

Alzheimer Disease
Therapeutics
scyllitol
Amyloid
Magnetic Resonance Spectroscopy
Phagocytosis
Astrocytes
Staining and Labeling
Prions
Amyloid beta-Peptides
Blood-Brain Barrier
Cricetinae
Fluorescent Antibody Technique
Permeability
Hippocampus
Immunohistochemistry
Mutation
Antibodies
Brain

Keywords

  • Alzheimer's disease
  • Amyloid
  • Antibody
  • Focused ultrasound
  • Magnetic resonance imaging
  • scyllo-Inositol

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Clinical Neurology
  • Developmental Biology

Cite this

Liu, M., Jevtic, S., Markham-Coultes, K., Ellens, N. P. K., O'Reilly, M. A., Hynynen, K., ... McLaurin, J. A. (2018). Investigating the efficacy of a combination Aβ-targeted treatment in a mouse model of Alzheimer's disease. Brain Research, 1678, 138-145. DOI: 10.1016/j.brainres.2017.10.015

Investigating the efficacy of a combination Aβ-targeted treatment in a mouse model of Alzheimer's disease. / Liu, Mingzhe; Jevtic, Stefan; Markham-Coultes, Kelly; Ellens, Nicholas P.K.; O'Reilly, Meaghan A.; Hynynen, Kullervo; Aubert, Isabelle; McLaurin, Jo Anne.

In: Brain Research, Vol. 1678, 01.01.2018, p. 138-145.

Research output: Research - peer-reviewArticle

Liu, M, Jevtic, S, Markham-Coultes, K, Ellens, NPK, O'Reilly, MA, Hynynen, K, Aubert, I & McLaurin, JA 2018, 'Investigating the efficacy of a combination Aβ-targeted treatment in a mouse model of Alzheimer's disease' Brain Research, vol 1678, pp. 138-145. DOI: 10.1016/j.brainres.2017.10.015
Liu M, Jevtic S, Markham-Coultes K, Ellens NPK, O'Reilly MA, Hynynen K et al. Investigating the efficacy of a combination Aβ-targeted treatment in a mouse model of Alzheimer's disease. Brain Research. 2018 Jan 1;1678:138-145. Available from, DOI: 10.1016/j.brainres.2017.10.015
Liu, Mingzhe ; Jevtic, Stefan ; Markham-Coultes, Kelly ; Ellens, Nicholas P.K. ; O'Reilly, Meaghan A. ; Hynynen, Kullervo ; Aubert, Isabelle ; McLaurin, Jo Anne. / Investigating the efficacy of a combination Aβ-targeted treatment in a mouse model of Alzheimer's disease. In: Brain Research. 2018 ; Vol. 1678. pp. 138-145
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