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Scanning ultrasound-mediated memory and functional improvements do not require amyloid-β reduction

ABSTRACT: A prevalent view in treating age-dependent disorders including Alzheimer’s disease (AD) is that the underlying amyloid plaque pathology must be targeted for cognitive improvements. In contrast, we report here that repeated scanning ultrasound (SUS) treatment at 1 MHz frequency can ameliorate memory deficits in the APP23 mouse model of AD without reducing amyloid-β (Aβ) burden. Different from previous studies that had shown Aβ clearance as a consequence of blood-brain barrier (BBB) opening, here, the BBB was not opened as no microbubbles were used. Quantitative proteomics and functional magnetic resonance imaging revealed that ultrasound induced long-lasting functional changes that correlate with the improvement in memory. Intriguingly, the treatment was more effective at a higher frequency (1MHz) than at a frequency within the range currently explored in clinical trials in AD patients (286 kHz). Together, our data suggest frequency-dependent bio-effects of ultrasound and a dissociation of cognitive improvement and Aβ clearance, with important implications for the design of trials for AD therapies.

INSTRUMENT(S): TripleTOF 6600

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain

DISEASE(S): Alzheimer's Disease

SUBMITTER: Laura Dagley

LAB HEAD: Professor Jürgen Götz

PROVIDER: PXD050248 | Pride | 2024-03-19

REPOSITORIES: Pride

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			Action	DRS
	010722_P32613_IDA_1.zip	Other
	010722_P32613_IDA_10.zip	Other
	010722_P32613_IDA_11.zip	Other
	010722_P32613_IDA_12.zip	Other
	010722_P32613_IDA_13.zip	Other

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Project description:Rationale: Epicardial adipose tissue (EAT) has been independently associated with non-calcified, high-risk coronary plaques in low-to intermediate risk subjects. Recently, a bidirectional communication was shown between EAT and diseased coronary arteries. In high-risk patients it is unknown whether quantitative measures of EAT can capture, and which molecular players are involved in this mutual interplay. Objective: In a high-risk population, we aimed to determine how the volume of EAT is linked to coronary artery disease (CAD) and to identify potential EAT-deregulated pathways in CAD patients specifically related to coronary artery calcification (CAC). Methods and Results: In a prospective cohort of 574 degenerative severe aortic stenosis patients referred to cardiac surgery, we quantified fat depots by computed tomography (CT) and performed a comparative quantitative proteomics of thoracic fat, including EAT, mediastinal (MAT) and subcutaneous (SAT) adipose tissues. We did not find an independent association of EAT volume with the severity, distribution and complexity of coronary stenosis in invasive coronary angiography. Although, EAT volume was correlated with high CAC, its cardiovascular risk factors-adjusted association was not significant. Taking as reference non-CAD matched-patients and compared to MAT and SAT, EAT proteomic signature of CAD was characterized by up-regulation of pro-calcifying annexins (Annexin A2, ANXA2), fatty acid binding transporters (FABP4) and inflammatory signaling proteins, and by down-regulation of fetuin-A and redox state regulatory enzymes. In EAT, ANXA2 regulation was positively correlated with CAC. EAT gene expression studies confirmed overexpression of ANXA2 and FABP4 in CAD, but no expression of FETUA was detected. Compared with non-CAD, fetuin-A circulating levels were higher in CAD, whereas no fetuin-A pericardial fluid differences were found. Conclusions: In this high-risk cohort, EAT presented an imbalance of pro-calcifying, pro-inflammatory and lipid transporters mediators. These local EAT-mediated regulatory mechanisms were not reflected by the CT volume of EAT alone.

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Scanning ultrasound-mediated memory and functional improvements do not require amyloid-β reduction

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