News
23/07/2024
Ultrasound Treatment: Advances in Alzheimer’s Therapy without Amyloid Reduction
For many years, Alzheimer’s disease (AD) research has fixated on the reduction of amyloid-β (Aβ) burden as the main therapeutic goal. In this context, opening the Blood-Brain Barrier (BBB) by ultrasound treatment with microbubbles allowed advances in neuronal Aβ clearance with FDA-approved antibodies such as aducanumab and donanemab. However, a recent study by Leinenga et al. (2024) proposes a new approach, showing that memory improvements in AD can occur even without reducing amyloid-β levels.
- Application of scanning ultrasound treatment without microbubbles (SUSonly) at low (lowF: 286 kHz) and high frequencies (highF: 1 MHz) to APP23 transgenic mice for eight weeks.
- Assessment of spatial memory and learning performance before and after treatment with SUS, followed by MRI brain scans and molecular analysis of investigated groups.
- In particular, the HighF group displayed significantly enhanced memory function despite no observable reduction in Aβ burden.
- fMRI and proteomic analyses reveal long-lasting structural and functional changes that correlate with spatial memory improvement.
Data suggest SUS-induced changes in brain/neuron plasticity and relocation of toxic tau species from the synapse to other compartments.
For this study, the authors used 11-month-old (75% male/25% female) wild-type and APP23 mice, the latter of which are commonly used as a model organism for AD research. Prior to SUS treatment, the mice were tested for spatial memory and learning performance in an active place avoidance (APA) test, which showed that wild-type mice had better learning performance than the transgenic mice. To assess long-term memory changes due to SUS treatment, the mice were subdivided into four groups:
- APP23 mice with eight weekly treatments at highF
- APP23 mice with eight weekly treatments at lowF
- APP23 mice with sham-treatment.
- WT mice with sham-treatment.
In the retest after eight weeks of treatment, highF APP23 mice showed a significant reduction of shocks on day 5 of the APA test (43% less than sham-treated APP23) and a significantly improved learning index (p = 0.027). Silver staining of brain sections and ELISA assays revealed no reduction of total plaque area and insoluble Aβ following both SUS treatments.
Proteomic analysis of cortical lysates revealed four expression clusters that were affected by SUS treatment (two upregulated, two downregulated). The severity of these alterations was even more prominent in highF compared to lowF, correlating with the APA results. These clusters contained proteins primarily involved in (golgi) vesicle transport, protein translocation and exocytosis as well as axonogenesis and development, and histone modification.
Several magnetic resonance imaging (MRI) approaches (fMRI, structural MRI, and diffusion MRI) were performed to review neuronal intra- and inter-network correlations, as well as brain microstructure. fMRI revealed improved memory-related hippocampal and salience networks in highF-treated mice. Scans of the brain microstructure also showed a SUS-induced response in brain tissue volumes. High US frequencies significantly reduced tissue volume, orientation dispersion index (ODI), neurite density index (NDI), and substantially increased brain fluid and ventricle volume.
As these observations were directly correlated with improved APA performance, the authors suggest an increase in neuronal plasticity as a response to SUS treatment. This was supported by the observation that, even though tau levels did not decrease in APP23 mice, its location shifted from the synapse to other compartments.
This research marks a significant departure from conventional Alzheimer’s treatments that typically focus on the biochemical reduction of cytotoxic Aβ. By demonstrating that cognitive improvements can be achieved through mechanisms dissociated from amyloid pathology, the study opens new avenues for non-invasive therapies that might circumvent the complexities and side effects associated with current pharmacological treatments.
This article refers to:
Leinenga G, To XV, Bodea L-G, Yousef J, Richter-Stretton G, Palliyaguru T, Chicoteau A, Dagley L, Nasrallah F, Götz J (2024) Scanning ultrasound-mediated memory and functional improvements do not require amyloid-β reduction. Mol Psychiatry 29:2408–2423. DOI: 10.1038/s41380-024-02509-5