Noel Rebecca L, Gorman Samantha L, Batts Alec J, Konofagou Elisa E
Department of Biomedical Engineering, Columbia University, New York, NY, United States.
Department of Radiology, Columbia University, New York, NY, United States.
Front Neurosci. 2023 Jul 27;17:1229683. doi: 10.3389/fnins.2023.1229683. eCollection 2023.
The amyloid-β (Aβ) hypothesis implicates Aβ protein accumulation in Alzheimer's disease (AD) onset and progression. However, therapies targeting Aβ have proven insufficient in achieving disease reversal, prompting a shift to focus on early intervention and alternative therapeutic targets. Focused ultrasound (FUS) paired with systemically-introduced microbubbles (μB) is a non-invasive technique for targeted and transient blood-brain barrier opening (BBBO), which has demonstrated Aβ and tau reduction, as well as memory improvement in models of late-stage AD. However, similar to drug treatments for AD, this approach is not sufficient for complete reversal of advanced, symptomatic AD. Here we aim to determine whether early intervention with FUS-BBBO in asymptomatic AD could delay disease onset. Thus, the objective of this study is to measure the protective effects of FUS-BBBO on anxiety, memory and AD-associated protein levels in female and male triple transgenic (3xTg) AD mice treated at an early age and disease state. Here we show that early, repeated intervention with FUS-BBBO decreased anxiety-associated behaviors in the open field test by 463.02 and 37.42% in male and female cohorts, respectively. FUS-BBBO preserved female aptitude for learning in the active place avoidance paradigm, reducing the shock quadrant time by 30.03 and 31.01% in the final long-term and reversal learning trials, respectively. Finally, FUS-BBBO reduced hippocampal accumulation of Aβ40, Aβ42, and total tau in females by 12.54, 13.05, and 3.57%, respectively, and reduced total tau in males by 18.98%. This demonstration of both cognitive and pathological protection could offer a solution for carriers of AD-associated mutations as a safe, non-invasive technique to delay the onset of the cognitive and pathological effects of AD.
淀粉样蛋白-β（Aβ）假说认为Aβ蛋白的积累与阿尔茨海默病（AD）的发病及进展有关。然而，事实证明，针对Aβ的治疗方法在实现疾病逆转方面并不充分，这促使人们转而关注早期干预和其他治疗靶点。聚焦超声（FUS）与全身注射的微泡（μB）相结合，是一种用于靶向和短暂打开血脑屏障（BBBO）的非侵入性技术，该技术已在晚期AD模型中证明可减少Aβ和tau蛋白，并改善记忆力。然而，与AD的药物治疗类似，这种方法不足以完全逆转晚期有症状的AD。在此，我们旨在确定在无症状AD中采用FUS-BBBO进行早期干预是否可以延缓疾病发作。因此，本研究的目的是测量FUS-BBBO对幼年和疾病状态下接受治疗的雌性和雄性三重转基因（3xTg）AD小鼠的焦虑、记忆和AD相关蛋白水平的保护作用。我们在此表明，早期重复进行FUS-BBBO干预可使雄性和雌性队列在旷场试验中与焦虑相关的行为分别减少463.02%和37.42%。FUS-BBBO在主动回避场所范式中保留了雌性的学习能力，在最后的长期和逆向学习试验中，分别将电击象限时间减少了30.03%和31.01%。最后，FUS-BBBO使雌性海马体中Aβ40、Aβ42和总tau的积累分别减少了12.54%、13.05%和3.57%，并使雄性总tau减少了18.98%。这种认知和病理保护作用的证明，可为AD相关突变携带者提供一种解决方案，作为一种安全、非侵入性的技术来延缓AD认知和病理效应的发作。
