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

• DOI: 10.1016/j.brainres.2017.10.015
• Publication Date: 2017-10-23T16:20:34Z
• Authors: Mingzhe Liu; Stefan Jevtic; Kelly Markham-Cou...; Nicholas P.K. Ellens; Meaghan A. O'Reilly; Kullervo Hynynen; Isabelle Aubert; JoAnne McLaurin
• Keywords: Amyloid beta-Peptides; Neurogenesis; Brain; Mice, Transgenic; Hippocampus; Magnetic Resonance Imaging; 3. Good health; Amyloid beta-Protein Precursor; Disease Models, Animal; Mice; 03 medical and health sciences; 0302 clinical medicine; Phagocytosis; Alzheimer Disease; Blood-Brain Barrier; Animals; Drug Therapy, Combination; Microglia; Inositol

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.