Low-intensity pulsed ultrasound enhances microglial-mediated Aβ clearance and synaptic preservation in an APP transgenic mouse model of Alzheimer's disease

Aug 14, 2025Experimental neurology

Low-intensity pulsed ultrasound may boost brain immune cells to clear amyloid and protect connections in a mouse model of Alzheimer's disease

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Abstract

LIPUS treatment significantly improved spatial learning and memory deficits in APP transgenic mice.

LIPUS reduced escape latency and increased platform crossings in the Morris water maze test, indicating better spatial memory.
The treatment significantly decreased amyloid plaque burden in the hippocampus and promoted microglial recruitment to these plaques.
LIPUS downregulated TNF-α expression while not affecting IL-6 levels, suggesting a mechanism for enhanced Aβ clearance without increasing neuroinflammation.
Increased expression of synaptophysin was observed in specific hippocampal regions, indicating preserved synaptic integrity.

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Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) plaque accumulation and neurofibrillary tangles, leading to neuroinflammation, synaptic dysfunction, and cognitive decline. Despite extensive research, current therapies for AD show limited efficacy. Low-intensity pulsed ultrasound (LIPUS) has emerged as a promising non-invasive therapeutic approach due to its neuroprotective and immunomodulatory properties. This study investigates the effects of LIPUS on Aβ pathology, neuroinflammation, and cognitive deficits in a transgenic AD mouse model. Twelve-month-old J20 transgenic mice expressing human amyloid precursor protein (APP) were used to model middle-to-late-stage AD. LIPUS was administered for 30 days, targeting the bilateral hippocampus. Spatial memory was assessed via the Morris water maze (MWM). Aβ plaque burden and synaptic integrity were quantified using immunofluorescence and Thioflavin-S staining. Western blot analysis evaluated neurotrophic factors, inflammatory markers, and synaptic proteins (PSD95). LIPUS treatment significantly improved spatial learning and memory deficits in APP transgenic mice, as evidenced by reduced escape latency and increased platform crossings in the MWM test. LIPUS significantly reduced hippocampal amyloid plaque burden and promoted microglial recruitment to Aβ plaques. Importantly, LIPUS downregulated TNF-α expression without affecting IL-6 levels, suggesting enhanced Aβ clearance without inducing neuroinflammation. Furthermore, LIPUS increased synaptophysin expression in the CA3-mossy fiber and dentate gyrus (DG) regions, while PSD95 levels remained unchanged. Our findings demonstrate that LIPUS enhances microglial-mediated Aβ clearance, preserves synaptic integrity, and improves cognitive function in a transgenic AD model. As a non-invasive modality capable of targeting deep brain structures, LIPUS holds promise as a potential therapeutic strategy for AD.

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Low-intensity pulsed ultrasound enhances microglial-mediated Aβ clearance and synaptic preservation in an APP transgenic mouse model of Alzheimer's disease

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