Ultrasound deep brain stimulation decelerates telomere shortening in Alzheimer's disease and aging mice

Abstract

Telomere length is a reliable biomarker for health and longevity prediction in both humans and animals. The common neuromodulation techniques, including deep brain stimulation (DBS) and optogenetics, have excellent spatial resolution and depth penetration but require implementation of electrodes or optical fibers. Therefore, it is important to develop methods for noninvasive modulation of telomere length. Herein, we reported on a new method for decelerating telomere shortening using noninvasive ultrasound deep brain stimulation (UDBS). Firstly, we found that UDBS could activate the telomerase-associated proteins in normal mice. Then, in the Alzheimer's disease mice, UDBS was observed to decelerate telomere shortening of the cortex and myocardial tissue and to effectively improve spatial learning and memory abilities. Similarly, UDBS was found to significantly slow down telomere shortening of the cortex and peripheral blood, and improve motor and cognitive functions in aging mice. Finally, transcriptome analysis revealed that UDBS upregulated the neuroactive ligand-receptor interaction pathway. Overall, the present findings established the critical role of UDBS in delaying telomere shortening and indicated that ultrasound modulation of telomere length may constitute an effective therapeutic strategy for aging and aging-related diseases.

Keywords: Aging; Alzheimer's disease(AD); Brain stimulation; Noninvasive ultrasound; Telomere length.

Graphical abstract

Fig. 1

Ultrasound deep brain stimulation (UDBS) modulates telomere length. (a) Schematic of UDBS alleviation of telomere shortening in aging and Alzheimer's disease (AD) mice. (b) Lateral and axial acoustic pressure distributions. (c) The time sequence of UDBS.

Fig. 2

Western blotting analyses of protein level of WRAP53 and TERT in the cortex of normal mice after UDBS. (a) Experiment schedule for 8-week-old mice. (b) UDBS increased the expression of WRAP53 and TERT in the cortex of normal mice. The data shown represent the mean ± SEM values for the indicated n. *p < 0.05, **p < 0.01, from independent-samples t-test.

Fig. 3

UDBS decelerates telomere shortening and improves spatial learning and memory abilities in AD mice. (a) Experiment schedule for 6-month-old amyloid precursor protein/presenilin 1 (APP/PS1) mice. (b) MWM test. UDBS increased the time in the target zone. (c) In the fear conditioning test, UDBS increased the percentage of freezing on Day 3. (d) Telomere length change of the cortex and myocardium after UDBS. The data shown represent the mean ± SEM for the indicated n. *p < 0.05, ****p < 0.0001, from independent-samples t-test.

Fig. 4

UDBS significantly alleviates telomere shortening and improves both motor and cognitive functions in aging mice. (a) Experiment schedule for 18-month-old aging mice. (b) In the open field test, UDBS significantly increased the total distance. (c) UDBS prominently increased the latency to fall in the rotarod test. (d) In the MWM test, UDBS significantly deceased the latency of the first entrance to the target. (e) The change of telomere length of both the cortex and blood by UDBS. (f) UDBS observably reduced the number of senescent cells under β-galactosidase staining. Scale bar: 200 μm. The data shown represent the mean ± SEM values for the indicated n. *p < 0.05, **p < 0.01, ****p < 0.0001, from independent-samples t-test.

Fig. 5

UDBS induces c-Fos expression in cortices and hippocampi of aging mice. Representative images of c-Fos protein in (a) cortex and (b) hippocampus after UDBS. Scale bar: left = 200 μm, right = 50 μm. The data shown represent the mean ± SEM values for the indicated n. ****p < 0.0001, from an independent-samples t-test.

Fig. 6

Transcriptome analysis of UDBS-modulated cortical tissue in aging mice. (a) Volcano plot showing differentially expressed genes (DEGs) identified in the UDBS group compared to the sham group in brain cortex. The significance cutoffs were set to p < 0.05, |log₂ FC| > 0.25. (b) Bubble map of Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of 785 differentially regulated genes identified in the UDBS and sham groups. (c) Analysis of PPI network construction and significant gene modules including brain-derived neurotrophic factor (BDNF), neuropeptide Y (NPY), and angiotensinogen (AGT) modules. (d) DEG heatmap. (e) Flash bar chart of upregulated genes. (f) Flash bar chart of downregulated genes.