Paris Brain Institute, ICM, Inserm U1127, CNRS UMR 7225, Sorbonne University, 75013 Paris, France.
Department of Neurosurgery, Sorbonne University, APHP, La Pitié-Salpêtrière Hospital, 75013 Paris, France.
Int J Mol Sci. 2023 Aug 3;24(15):12411. doi: 10.3390/ijms241512411.
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.
阿尔茨海默病（AD）是痴呆症的主要病因。目前尚无治疗方法能产生显著的临床效果。外周给药治疗中枢神经系统疾病的主要障碍与血脑屏障（BBB）有关。研究表明，与微泡结合的超声可以短暂且安全地打开 BBB。在 AD 小鼠模型中，单独使用 BBB 开放而不联合使用其他药物可能足以减少病变并减轻认知能力下降。然而，这些治疗效果目前主要在淀粉样蛋白的临床前小鼠模型中进行评估，而在 tau 病变中记录较少。因此，本研究旨在通过低强度脉冲超声（LIPU）评估重复 BBB 开放对 P301S tau 转基因小鼠的影响，主要有两个观察指标：tau 阳性病变和小胶质细胞。我们的结果表明，LIPU 诱导的 BBB 开放并不能减少 tau 病变，甚至可能加剧特定脑区病理性 tau 的积累。此外，在 P301S 小鼠中，LIPU-BBB 开放强烈降低了脑实质中的小胶质细胞密度，提示具有抗炎作用。这些结果为未来在动物模型和 AD 患者中使用 LIPU-BBB 开放联合药物治疗等方法提供了基础。
