FOCUSED ULTRASOUND RESCUES MEMORY DEFICITS IN THE 5XFAD MOUSE MODEL OF ALZHEIMER’S DISEASE WITHOUT LOWERING AMYLOID-Β

Despite extensive research, current treatments for Alzheimer’s disease (AD) offer only modest benefits, highlighting the need for novel therapeutic approaches. Focused ultrasound (FUS), is a non-invasive neuromodulation technique that has shown promise in improving memory deficits in pre-clinical models and patients with AD. When delivered at a pulse repetition frequency (PRF) of 40 Hz, FUS has been shown to entrain gamma oscillations, which has been associated with increased amyloid-β clearance and enhanced long-term potentiation. However, it remains unclear whether cognitive improvements after FUS are solely dependent on the removal of amyloid-β. It is also unknown whether these cognitive improvements are consistent across sexes.
Here, we investigated whether FUS stimulation rescues cognitive deficits in the 5XFAD mouse model of AD and whether any behavioural improvements are amyloid-dependent and sex-specific. 6-month-old male and female 5XFADxThy1-eGFP mice were treated with FUS (centre frequency: 1MHz, pressure: 0.7MPa, pulse length: 10ms, PRF: 40Hz) for five consecutive days. Cognitive performance was assessed using the openfield, novel object recognition and Y-maze tests. Amyloid-β levels were subsequently quantified by western blot, ELISA and immunohistochemistry.
FUS stimulation rescued deficits in recognition and spatial memory in male mice only. No changes in locomotion or anxiety-like behaviour were observed in either sex after treatment. There were no differences in amyloid-β in the hippocampus or cortex between treatment groups.
Together, these findings demonstrate that FUS stimulation can rescue memory deficits independently of changes in amyloid-β burden, supporting its potential as a novel non-invasive therapeutic strategy for improving cognitive function in AD.