Effects of Low-Intensity Pulsed Ultrasound-Induced Blood-Brain Barrier Opening in P301S Mice Modeling Alzheimer's Disease Tauopathies

Alzheimer's disease (AD) is the leading cause of dementia. No treatments have led to clinically meaningful impacts. A major obstacle for peripherally administered therapeutics targeting the central nervous system is related to the blood-brain barrier (BBB). Ultrasounds associated with microbubbles have been shown to transiently and safely open the BBB. In AD mouse models, the sole BBB opening with no adjunct drugs may be sufficient to reduce lesions and mitigate cognitive decline. However, these therapeutic effects are for now mainly assessed in preclinical mouse models of amyloidosis and remain less documented in tau lesions. The aim of the present study was therefore to evaluate the effects of repeated BBB opening using low-intensity pulsed ultrasounds (LIPU) in tau transgenic P301S mice with two main readouts: tau-positive lesions and microglial cells. Our results show that LIPU-induced BBB opening does not decrease tau pathology and may even potentiate the accumulation of pathological tau in selected brain regions. In addition, LIPU-BBB opening in P301S mice strongly reduced microglia densities in brain parenchyma, suggesting an anti-inflammatory action. These results provide a baseline for future studies using LIPU-BBB opening, such as adjunct drug therapies, in animal models and in AD patients.

Automated summary

Alzheimer's disease is a major cause of dementia with no effective treatments available. The blood-brain barrier is a major obstacle for delivering therapeutics to the central nervous system. Ultrasounds with microbubbles have been shown to temporarily and safely open the blood-brain barrier. Opening the blood-brain barrier without adjunct drugs may be sufficient to reduce lesions and improve cognitive decline in AD mouse models.