Focused ultrasound delivery of BAM-10 to the brain reduces Aβ plaque pathology in TgCRND8 mice.

<p>Coronal sections were stained with streptavadin-Cy2 for (<b>A</b>) biotinylated BAM-10 and (<b>B</b>) anti-Aβ antibody 6F3D for plaques to demonstrate that 6F3D binds to plaques which are strongly (arrows) and weakly (arrowheads) positive for BAM-10 (<b>C</b>). Once it was confirmed that BAM-10 does not interfere with 6F3D plaque detection, sections for mice in each treatment group were stained with 6F3D and the stereology software was used to draw contours outlining the FUS-targeted region (determined from MRI post-treatment scans) on the right side of the brain and an equivalent region on the contralateral side (<b>D</b>). Plaques were counted and measured at high magnification (<b>E</b>), using stereological methods. In 4 days, the mean (<b>F</b>) count, (<b>G</b>) size and (<b>H</b>) surface area of Aβ plaques on the right, MRIgFUS-targeted side of the brain was consistently reduced in comparison to the left side of the brain only for the BAM-10/FUS-treated mice (<b>F–H</b>; n = 6, paired t-tests, p = 0.008, p = 0.048 and p = 0.003, respectively). This difference is unique to BAM-10/FUS treatment as there was no significant difference between right and left side of the brain in mice from other treatment groups (<b>F′–H′</b>: BAM-10 treated group, n = 6, paired t-tests, p = 0.294, p = 0.941 and p = 0.402; <b>F″–H″</b>: Untreated group, n = 6, paired t-tests, p = 0.502, p = 0.690, p = 0.610). Scale bars: A–C = 100 µm (inset = 20 µm); D = 1 mm; E = 50 µm.</p

Magnetic resonance imaging-guided focused ultrasound (MRIgFUS) increases the permeability of the blood brain barrier (BBB).

<p>T1-weighted contrast-enhanced MRI scans were used to position ultrasound foci prior to treatment (<b>A</b>) and following transcranial FUS (<b>B–D</b>), were used to monitor the entry of gadolinium in the brain. Mice were positioned in a supine position (<b>B</b>) and injected in the tail vein with microbubbles and gadolinium while ultrasound was applied to 4 aligned spots on the right hemisphere of the brain. Increased BBB permeability was monitored by MRI, visualizing contrast enhancement by the influx of gadolinium (<b>B–D</b>). [A–D: 128×128, TE/TR = 10.4/500.0, FOV = 4cm, Slice 1mm, ETL = 4, 3NEX]. Scale bars: A, C, D = 0.5 cm.</p

Aβ levels in TgCRND8 mice after one BAM-10/FUS treatment.

<p>Cortical homogenates were analyzed for total Aβ₄₀ (<b>A</b>), soluble Aβ₄₀ (<b>B</b>), total Aβ₄₂ (<b>C</b>) and soluble Aβ₄₂ (<b>D</b>). There was no significant difference detected any Aβ species and fractions between the left and right hemispheres.</p