2. Academic Validation
  3. Restoration of autophagy-lysosomal function via transcranial focused ultrasound stimulation ameliorates β-amyloid pathology and cognitive deficits in an Alzheimer's disease model

Restoration of autophagy-lysosomal function via transcranial focused ultrasound stimulation ameliorates β-amyloid pathology and cognitive deficits in an Alzheimer's disease model

  • Ultrasonics. 2026 Sep:165:108075. doi: 10.1016/j.ultras.2026.108075.
Mengke Wang 1,  Baochen Zhang 2,  Renhao Guo 3,  Haiqin Wang 4,  Di Wu 5,  Xiaoqian Peng 6,  Hongsong Guo 7,  Jiawei Duan 8,  Weina Yang 9,  Pengyu Ren 10,  Siyuan Zhang 11
Affiliations

Affiliations

  • 1 The Key Laboratory of Biomedical Information Engineering of Ministry of Education, Department of Biomedical Engineering, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, China. Electronic address: [email protected].
  • 2 The Key Laboratory of Biomedical Information Engineering of Ministry of Education, Department of Biomedical Engineering, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, China. Electronic address: [email protected].
  • 3 The Key Laboratory of Biomedical Information Engineering of Ministry of Education, Department of Biomedical Engineering, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, China. Electronic address: [email protected].
  • 4 The Key Laboratory of Biomedical Information Engineering of Ministry of Education, Department of Biomedical Engineering, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, China. Electronic address: [email protected].
  • 5 The Department of Neurosurgery, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China. Electronic address: [email protected].
  • 6 The Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, China. Electronic address: [email protected].
  • 7 The Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, China. Electronic address: [email protected].
  • 8 The Key Laboratory of Biomedical Information Engineering of Ministry of Education, Department of Biomedical Engineering, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, China. Electronic address: [email protected].
  • 9 The Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, China. Electronic address: [email protected].
  • 10 The Department of Neurosurgery, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China; The Sichuan Digital Economy Industry Development Research Institute, Chengdu, Sichuan, China. Electronic address: [email protected].
  • 11 The Key Laboratory of Biomedical Information Engineering of Ministry of Education, Department of Biomedical Engineering, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, China. Electronic address: [email protected].
PMID: 41886893 DOI: 10.1016/j.ultras.2026.108075
Abstract

Transcranial focused ultrasound (FUS) is a non-invasive neuromodulation technique that regulates intracellular functions and treats brain disorders. In Alzheimer's disease (AD), impaired autophagy-lysosomal pathway (ALP) function leads to the accumulation of β-amyloid (Aβ). However, the potential of FUS alone to alleviate AD pathology by restoring ALP function remains unexplored. In this study, sixteen male transgenic mice with five familial Alzheimer's disease mutations (5×FAD) received bilateral FUS targeting the hippocampus and were compared with sixteen age-matched untreated male 5×FAD mice. Cognitive function was evaluated using behavioral tests, and Aβ pathology was analyzed by immunofluorescence. RNA Sequencing, western blotting, and electron microscopy were employed to assess the effects of FUS on the ALP. The results indicated that FUS reduced Aβ deposition and ameliorated cognitive deficits. Compared with the AD group, FUS treatment significantly reduced escape latency by 40.9% (p = 0.010), increased the novel object recognition index by 38.2% (p = 0.016), and increased spontaneous alternation by 18.2% (p = 0.009). Critically, FUS enhanced lysosomal biogenesis and improved autophagosome-lysosome fusion, increasing colocalization efficiency from 28.07 ± 3.73% to 53.22 ± 4.85% in the cortex (p = 0.009) and from 31.95 ± 3.65% to 48.00 ± 2.18% in the hippocampus (p = 0.026). It also promoted the nuclear translocation of transcription factor EB (TFEB). Moreover, the ALP antagonist chloroquine (CQ) suppressed the beneficial effects of FUS, indicating that FUS exerts therapeutic effects in an ALP-dependent manner. Our findings demonstrate that restoring ALP via FUS is a crucial mechanism for mitigating Aβ pathology.

Keywords

Alzheimer’s disease; Autophagy-lysosomal pathway; Lysosomal function; Transcranial focused ultrasound neuromodulation; β-amyloid.

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