Unilateral Focused Ultrasound-Induced Blood-Brain Barrier Opening Reduces Phosphorylated Tau from The rTg4510 Mouse Model.

Authors: Karakatsani ME, Kugelman T, Ji R, Murillo M, Wang S, Niimi Y, Small SA, Duff KE, Konofagou EE

The neuropathological hallmarks of Alzheimer's disease include amyloid plaques and neurofibrillary tangles. Tau pathology correlates well with impaired neuronal activity and dementia. Focused ultrasound coupled with systemic administration of microbubbles has previously been shown to open the blood-brain barrier and induce an immune response, which, in an amyloid AD mouse model, resulted in the reduction of the amyloid brain load. Methods: In this study, we investigated the effect of focused ultrasound at the early stages of tau pathology (pre-tangle) in the rTg4510 mouse model. Results: Reduction of phosphorylated tau from the hippocampal formation processes, and particularly the pyramidal CA1 neurons, was noted in the ultrasound-treated brains without an associated increase in the phosphorylated tau-affected cell somas, typically associated with disease progression. Attenuation of the pathology was found to correlate well with the ultrasound-initiated immune response without compromising neuronal integrity. Unilateral ultrasound application resulted in a bilateral effect indicating a broader reduction of the phosphorylated tau. Conclusion: Findings presented herein reinforce the premise of ultrasound in reducing tau pathology and thus curbing the progression of Alzheimer's disease.

Introduction

Purpose Drug delivery with BBB opening

Study Objective To determine whether unilateral focused ultrasound–induced BBB opening at early-stage tau pathology can reduce phosphorylated human tau in the hippocampus of rTg4510 mice and elicit an immune response.

Animal model / Human subject Mouse (Mus musculus), rTg4510 transgenic strain, age None, sex None

Disease model Alzheimer's disease

Targeted brain region(s) Hippocampal formation

Outcomes and Safety

Summary of Outcomes Repeated focused ultrasound (FUS) with systemic microbubbles transiently opened the BBB in rTg4510 mice and significantly reduced phosphorylated tau in the hippocampus—particularly shortening p‑tau‑positive CA1 neuronal processes—while increasing microglial/macrophage activation and apparent microglial engulfment of p‑tau without detectable neuronal damage; unilateral sonication produced bilateral effects. The study tested a single safe FUS+microbubble sonication regimen (repeated weekly applications) and found it effective.

Safety-related matter No adverse effects were observed: FUS-induced BBB opening showed comparable volumes across groups with no evidence of edema on T2-weighted scans and did not compromise neuronal integrity at the detection sensitivity used, indicating the procedure was tolerable.

Brain Region

Ultrasound Parameters

Focal Characteristics Focal depth: None; Focal length: None; Aperture size: None

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