Voluntary Swimming Reduces Amyloid Pathology in an Alzheimer's Mouse Brain: An Integrated Amyloid PET/CT and Light-Sheet Microscopy Evaluation.

Abstract

Despite numerous observational studies linking exercise to reduced dementia risk, RCT level evidences remain limited to validate physical activity as an effective resistance-augmenting lifestyle intervention. However, transgenic Alzheimer's disease (AD) mouse models circumvent the confounding factors and adherence challenges of human studies by offering rigorous control of exercise regimens, and the capability for advanced three-dimensional imaging to precisely quantify amyloid burden. Using an integrated platform combining [18F]florapronol PET/CT with light-sheet fluorescence microscopy (LSFM) and tissue clearing techniques, we investigated the effect of a 7-wk voluntary swimming on decreasing beta-amyloid (Aβ) pathology in hAPPsw AD mouse. In a prospective interventional study, 20 female AD mice with a mean ± SD age of 63.7 ± 3.4 wk were randomly divided into an intervention and a nonexposure control group (each n = 10). A 7-wk voluntary swimming regimen was conducted in 15-cm deep wavy using wave generators, starting with one 10-min session daily during week 1, progressing to six 10-min sessions per day by week 7. The standardized uptake value ratios (SUVRs) were measured using [18F]florapronol PET/CT. The excised brains were then prepared using hydrophilic tissue clearing and volume immunostaining with thioflavin S for Aβ (488 nm). In LSFM imaging, brain Aβ quantitative and morphological parameters were quantified using Imaris-based 3D volumetric surface model. In [18F]florapronol PET/CT, swim group exhibited mildly decreased uptake compared with control, although neocortical SUVR differences lacked statistical significance (swim: 1.09 ± 0.14; control: 1.21 ± 0.16, P = 0.100). In LSFM imaging, swim group presented significantly lower Aβ accumulation, as indicated by decreases in total surface volume (swim, 76,401,421 ± 14,403,875 μm3; control, 99,602,785 ± 9,163,020 μm3; P < 0.001) and plaque number (swim, 88,620 ± 15,608; control, 104,612 ± 14,311; P = 0.007), than nonexposure control group. There were no statistically significant differences in individual plaque area and volume or in the morphological shape parameters of amyloid particles, such as ellipticity and sphericity. We first demonstrated that a 7-wk voluntary swimming is an effective intervention for reducing Aβ pathology in a mouse model of advanced AD.