Abstract
<title>Abstract</title> <p>A major obstacle to effective Alzheimer’s disease therapy is the limited ability to deliver therapeutics across the blood-brain barrier. Focused ultrasound with microbubbles can transiently increase BBB permeability, and rapid short-pulse (RaSP) sequences have been shown to improve the safety and efficiency of this approach. Here, we investigated whether repeated RaSP-ultrasound treatments could deliver the cobalt-based compound CoLAm2, an inhibitor of amyloid-β (Aβ) oligomerization, to the brains of 5xFAD mice. Five-month-old mice received three weekly treatments consisting of intravenous CoLAm2 (5 mg/kg) and targeted BBB opening in the left hippocampus using RaSP ultrasound sequences. Immunohistochemistry demonstrated a 60.5% reduction in Aβ plaque area in mice receiving combined focused ultrasound and CoLAm2 compared with ultrasound-only, drug-only, and untreated controls. Ultrasound-only treatment also reduced aggregated Aβ by 35.6%, as assessed by Thioflavin S staining. Open field and novel object recognition tests detected no adverse effects on locomotor activity, anxiety-like behaviour, or cognition following repeated treatments. These findings demonstrate that repeated RaSP-ultrasound enables safe delivery of a small-molecule therapeutic across the BBB and enhances its anti-amyloid effects in a mouse model of Alzheimer’s disease, supporting further investigation of this approach for neurological disorders.</p>