Hepatic-targeted low-intensity pulsed ultrasound attenuates cerebral amyloidosis via upregulating insulin-degrading enzyme.

This study aimed to investigate whether low-intensity pulsed ultrasound (LIPUS) targeted at the liver can alleviate cerebral Aβ pathology by improving peripheral metabolism and enhancing hepatic Aβ clearance in a comorbid mouse model. 5xFAD transgenic mice were fed a high-fat diet (HFD) to induce peripheral IR. Mice received hepatic LIPUS intervention for four weeks. Outcomes were assessed using metabolic tests, in vivo and ex vivo fluorescence imaging of Aβ trafficking, neuropathological analysis, proteomics, and the Morris water maze. LIPUS ameliorated HFD-induced IR, hepatic steatosis, and pancreatic islet hyperplasia. It upregulated hepatic expression of Aβ-clearance proteins (IDE, LRP-1), enhanced peripheral Aβ catabolism, and reduced Aβ infiltration into the brain. Consequently, LIPUS attenuated cerebral Aβ deposition, neuronal apoptosis, and partially rescued spatial learning and memory deficits. Proteomic analysis confirmed systemic upregulation of metabolic and clearance pathways. Hepatic LIPUS modulates the peripheral metabolism-central clearance axis, reducing brain Aβ burden and improving cognitive function. This non-invasive approach presents a novel strategy for AD, particularly in the context of metabolic dysfunction.