Abstract
BackgroundAducanumab is an anti-amyloid-β (Aβ) antibody that achieved reduced amyloid pathology in Alzheimer’s disease (AD) trials; however, it is controversial whether it also improved cognition, which has been suggested would require a sufficiently high cumulative dose of the antibody in the brain. Therapeutic ultrasound, in contrast, has only begun to be investigated in human AD clinical trials. We have previously shown that scanning ultrasound in combination with intravenously injected microbubbles (SUS), which temporarily and safely opens the blood-brain barrier (BBB), removes amyloid and restores cognition in APP23 mice. However, there has been no direct testing of how the effects of SUS compare to immunotherapy or whether a combination therapy is more effective.MethodsIn a study comprising four treatment arms, we tested the efficacy of an Aducanumab analog, Adu, both in comparison to SUS, and as a combination therapy, in APP23 mice (aged 13–22 months), using sham as a control. The active place avoidance (APA) test was used to test spatial memory, and histology and ELISA were used to measure amyloid. Brain antibody levels were also determined.ResultsWe found that both Adu and SUS reduced the total plaque area in the hippocampus with no additive effect observed with the combination treatment (SUS + Adu). Whereas in the cortex where there was a trend towards reducing the total plaque area from either Adu or SUS, only the combination treatment yielded a statistically significant decrease in total plaque area compared to sham. Only the SUS and SUS + Adu groups included animals that had their plaque load reduced to below 1% from above 10%. There was a robust improvement in spatial memory for the SUS + Adu group only, and in this group the level of Adu, when measured 3 days post-treatment, was 5-fold higher compared to those mice that received Adu on its own.Together, these findings suggest that SUS should be considered as a treatment option for AD. Alternatively, a combination trial using Aducanumab together with ultrasound to increase brain levels of the antibody may be warranted.
Highlights
Aducanumab is an anti-amyloid-β (Aβ) antibody that achieved reduced amyloid pathology in Alzheimer’s disease (AD) trials; it is controversial whether it improved cognition, which has been suggested would require a sufficiently high cumulative dose of the antibody in the brain
Generation of Aducanumab analog and application The Aducanumab analog Adu was generated by grafting the VH and VL chains of Aducanumab onto a mouse IgG backbone and expressing this in Expi293 cells
Aducanumab does not increase the number of microhemorrhages in APP23 mice We investigated whether Adu or scanning ultrasound (SUS) + Adu treatment increased the occurrence of microhemorrhages as detected by Perl’s Prussian blue staining for clusters of hemosiderin deposits and found that microbleeds were common in APP23 mice, they did not increase in response to treatment (F3,16 = 0.94, p = 0.44, one-way ANOVA) (Fig. 3b)
Summary
Aducanumab is an anti-amyloid-β (Aβ) antibody that achieved reduced amyloid pathology in Alzheimer’s disease (AD) trials; it is controversial whether it improved cognition, which has been suggested would require a sufficiently high cumulative dose of the antibody in the brain. Aducanumab is an anti-Aβ antibody that targets Aβ aggregates including insoluble fibrils and soluble oligomers, by binding to the amino-terminus of Aβ at residues 3–7 in a shallow pocket in the antibody [4] This human IgG1 antibody was isolated from the B cells of cognitively healthy elderly humans and has low affinity for monomeric Aβ [5]. Biogen is currently seeking U.S Food and Drug Administration (FDA) approval for Aducanumab and may be granted conditional approval of the therapy pending a post-market commitment of a phase IIIB re-dosing trial that has recently been launched. If approved, it will be the first anti-amyloid agent and first antibody treatment for AD. Sevigny et al [5] demonstrated 50% plaque reduction in 9.5– 15.5-month-old amyloid precursor protein (APP) mutant Tg2576 mice after treating with a mouse IgG2a Aducanumab analog; the effects of the immunotherapy on behavioral read-outs in mouse models have not been reported
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