| First Author | Shen Y | Year | 2020 |
| Journal | Theranostics | Volume | 10 |
| Issue | 25 | Pages | 11794-11819 |
| PubMed ID | 33052247 | Mgi Jnum | J:313523 |
| Mgi Id | MGI:6798207 | Doi | 10.7150/thno.44152 |
| Citation | Shen Y, et al. (2020) Ultrasound with microbubbles improves memory, ameliorates pathology and modulates hippocampal proteomic changes in a triple transgenic mouse model of Alzheimer's disease. Theranostics 10(25):11794-11819 |
| abstractText | Alzheimer's disease (AD) is a progressive neurodegenerative disease manifested by cognitive impairment. As a unique approach to open the blood-brain barrier (BBB) noninvasively and temporarily, a growing number of studies showed that low-intensity focused ultrasound in combination with microbubbles (FUS/MB), in the absence of therapeutic agents, is capable of ameliorating amyloid or tau pathology, concurrent with improving memory deficits of AD animal models. However, the effects of FUS/MB on both the two pathologies simultaneously, as well as the memory behaviors, have not been reported so far. Methods: In this study, female triple transgenic AD (3xTg-AD) mice at eight months of age with both amyloid-beta (Abeta) deposits and tau phosphorylation were treated by repeated FUS/MB in the unilateral hippocampus twice per week for six weeks. The memory behaviors were investigated by the Y maze, the Morris water maze and the step-down passive avoidance test following repeated FUS/MB treatments. Afterwards, the involvement of Abeta and tau pathology were assessed by immunohistochemical analysis. Neuronal health and phagocytosis of Abeta deposits by microglia in the hippocampus were examined by confocal microscopy. Further, hippocampal proteomic alterations were analyzed by employing two-dimensional fluorescence difference gel electrophoresis (2D-DIGE) combined with mass spectrometry. Results: The three independent memory tasks were indicative of evident learning and memory impairments in eight-month-old 3xTg-AD mice, which developed intraneuronal Abeta, extracellular diffuse Abeta deposits and phosphorylated tau in the hippocampus and amygdala. Following repeated FUS/MB treatments, significant improvement in learning and memory ability of the 3xTg-AD mice was achieved. Amelioration in both Abeta deposits and phosphorylated tau in the sonicated hemisphere was induced in FUS/MB-treated 3xTg-AD mice. Albeit without increase in neuron density, enhancement in axonal neurofilaments emerged from the FUS/MB treatment. Confocal microscopy revealed activated microglia engulfing Abeta deposits in the FUS/MB-treated hippocampus. Further, proteomic analysis revealed 20 differentially expressed proteins, associated with glycolysis, neuron projection, mitochondrial pathways, metabolic process and ubiquitin binding etc., in the hippocampus between FUS/MB-treated and sham-treated 3xTg-AD mice. Conclusions: Our findings reinforce the positive therapeutic effects on AD models with both Abeta and tau pathology induced by FUS/MB-mediated BBB opening, further supporting the potential of this treatment regime for clinical applications. |
