Restoration of autophagy-lysosomal function via transcranial focused ultrasound stimulation ameliorates β-amyloid pathology and cognitive deficits in an Alzheimer’s disease model
Mengke Wang, Baochen Zhang, Renhao Guo, Haiqin Wang, Di Wu, Xiaoqian Peng, Hongsong Guo, Jiawei Duan, Weina Yang, Pengyu Ren, Siyuan Zhang
Ultrasonics 2026 · 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.
Abstract via europepmc.
Exposures
Exposure 1: Bilateral hippocampal FUS in 5xFAD mice
Target: hippocampus — “bilateral FUS targeting the hippocampus”
Device: not reported
| Waveform | pulsed | |
|---|---|---|
| Fundamental frequency (kHz) | 1,060 | ✓✓✓ |
| Pulse duration (ms) | 2 | ✓✓✓ |
| Pulse repetition frequency (Hz) | 250 | ✓✓✓⚑ |
| Duty cycle (%) | not reportedpulse duration × PRF gives 50% | ⚑ |
| Sonication duration (s) | 0.2 | ✓✓✓⚑ |
| Free-field pressure (kPa) | not reported | |
|---|---|---|
| Free-field Isppa (W/cm²) | not reported | |
| Free-field Ispta (W/cm²) | not reported | |
| In-situ estimate | not reportedsingle value | |
| In-situ pressure (kPa) | 320 | ✓✓✓ |
| In-situ Isppa (W/cm²) | not reported | |
| In-situ Ispta (W/cm²) | not reported | |
| Isppa, domain unspecified (W/cm²) | 3.32 | ✓✓✓⚑ |
| Ispta, domain unspecified (W/cm²) | 0.064 | ✓✓✓ |
Pulse interval 5 s, sonication duration 200 ms, pulse repetition period 4 ms, pulse duration 2 ms; bilateral stimulation 10 min/day each side for 1 month under 2% isoflurane.
Flags from extraction
n_subjects— Group sizes given: AD+FUS n=16 and AD+FUS+CQ n=11 (both exposed); abstract also says sixteen FUS mice. Total exposed not stated, so group sizes listed; figure legends show n=4 to 7 per analysis.exposures[0].timing.pulse_repetition_frequency_hz— Paper gives a pulse repetition period of 4 ms, recorded as 250 Hz (unit conversion).exposures[0].timing.duty_cycle_pct— Duty cycle not stated.exposures[0].timing.sonication_duration_s— 200 ms is the sonication duration within a 5 s pulse interval; 10 min per side per day for one month.exposures[0].in_situ.method— 0.32 MPa called 'intracranial' with 18% transcranial attenuation mentioned, but the paper does not say it was derated, simulated or measured.exposures[0].unspecified_domain.isppa_w_cm2— Isppa and Ispta given with no domain stated.exposures[0].target.terms— Bilateral hippocampus by atlas alignment; the elliptical focal region may also include adjacent tissue.