Ultrasound with microbubbles improves memory, ameliorates pathology and modulates hippocampal proteomic changes in a triple transgenic mouse model of Alzheimer's disease

Oct 14, 2020Theranostics

Ultrasound with microbubbles may improve memory, reduce disease signs, and change protein patterns in the memory system of Alzheimer's mice

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Abstract

Repeated low-intensity focused ultrasound with microbubbles improved learning and memory in 3×Tg-AD mice after six weeks of treatment.

Eight-month-old 3×Tg-AD mice exhibited significant learning and memory impairments, characterized by amyloid-β deposits and phosphorylated tau in the hippocampus.
FUS/MB treatment led to notable improvements in memory behaviors across three independent tasks.
Both amyloid-β deposits and phosphorylated tau were reduced in the treated hemisphere following FUS/MB application.
The treatment resulted in enhanced axonal neurofilaments, though no increase in neuron density was observed.
Activated microglia were found engulfing amyloid-β deposits in the hippocampus of FUS/MB-treated mice.
Proteomic analysis identified 20 differentially expressed proteins linked to various cellular processes in the hippocampus of treated versus sham-treated mice.

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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.In this study, female triple transgenic AD (3×Tg-AD) mice at eight months of age with both amyloid-β (Aβ) 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 Aβ and tau pathology were assessed by immunohistochemical analysis. Neuronal health and phagocytosis of Aβ 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.The three independent memory tasks were indicative of evident learning and memory impairments in eight-month-old 3×Tg-AD mice, which developed intraneuronal Aβ, extracellular diffuse Aβ deposits and phosphorylated tau in the hippocampus and amygdala. Following repeated FUS/MB treatments, significant improvement in learning and memory ability of the 3×Tg-AD mice was achieved. Amelioration in both Aβ deposits and phosphorylated tau in the sonicated hemisphere was induced in FUS/MB-treated 3×Tg-AD mice. Albeit without increase in neuron density, enhancement in axonal neurofilaments emerged from the FUS/MB treatment. Confocal microscopy revealed activated microglia engulfing Aβ 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 3×Tg-AD mice.Our findings reinforce the positive therapeutic effects on AD models with both Aβ and tau pathology induced by FUS/MB-mediated BBB opening, further supporting the potential of this treatment regime for clinical applications. Methods: Results: Conclusions:

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Ultrasound with microbubbles improves memory, ameliorates pathology and modulates hippocampal proteomic changes in a triple transgenic mouse model of Alzheimer's disease

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