Neuroprotective effects of resistance physical exercise on the APP/PS1 mouse model of Alzheimer’s disease

Abstract

IntroductionPhysical exercise has beneficial effects by providing neuroprotective and anti-inflammatory responses to AD. Most studies, however, have been conducted with aerobic exercises, and few have investigated the effects of other modalities that also show positive effects on AD, such as resistance exercise (RE). In addition to its benefits in developing muscle strength, balance and muscular endurance favoring improvements in the quality of life of the elderly, RE reduces amyloid load and local inflammation, promotes memory and cognitive improvements, and protects the cortex and hippocampus from the degeneration that occurs in AD. Similar to AD patients, double-transgenic APPswe/PS1dE9 (APP/PS1) mice exhibit Αβ plaques in the cortex and hippocampus, hyperlocomotion, memory deficits, and exacerbated inflammatory response. Therefore, the aim of this study was to investigate the effects of 4 weeks of RE intermittent training on the prevention and recovery from these AD-related neuropathological conditions in APP/PS1 mice.MethodsFor this purpose, 6-7-month-old male APP/PS1 transgenic mice and their littermates, negative for the mutations (CTRL), were distributed into three groups: CTRL, APP/PS1, APP/PS1+RE. RE training lasted four weeks and, at the end of the program, the animals were tested in the open field test for locomotor activity and in the object recognition test for recognition memory evaluation. The brains were collected for immunohistochemical analysis of Aβ plaques and microglia, and blood was collected for plasma corticosterone by ELISA assay.ResultsAPP/PS1 transgenic sedentary mice showed increased hippocampal Aβ plaques and higher plasma corticosterone levels, as well as hyperlocomotion and reduced central crossings in the open field test, compared to APP/PS1 exercised and control animals. The intermittent program of RE was able to recover the behavioral, corticosterone and Aβ alterations to the CTRL levels. In addition, the RE protocol increased the number of microglial cells in the hippocampus of APP/PS1 mice. Despite these alterations, no memory impairment was observed in APP/PS1 mice in the novel object recognition test.DiscussionAltogether, the present results suggest that RE plays a role in alleviating AD symptoms, and highlight the beneficial effects of RE training as a complementary treatment for AD.

An Interaction between Brain-Derived Neurotrophic Factor and Stress-Related Glucocorticoids in the Pathophysiology of Alzheimer’s Disease

“…Stress management techniques, such as mindfulness-based interventions and cognitive-behavioral therapy, may be explored as preventive measures for individuals at risk of AD [140]. These approaches could reduce stress-related GR fluctuations and potentially delay disease onset [146,147]. Lifestyle modifications, including regular physical exercise, a balanced diet, and adequate sleep, may also have a significant impact on GC regulation [148].…”

“…Lifestyle modifications, including regular physical exercise, a balanced diet, and adequate sleep, may also have a significant impact on GC regulation [148]. These factors can help maintain a healthy stress response system and mitigate the effects of chronic stress on neuroinflammation, oxidative stress, and Aβ/Tau pathology [147,149].…”

Experimental laboratory models as tools for understanding modifiable dementia risk

“… 197 Resistance exercise after the onset of pathology can reduce hippocampal Aβ load, increase hippocampal microglia recruitment, and normalize motor and cognitive behaviors in APP/PS1 mice. 200 , 221 Treadmill exercise before and during ICV delivery of Aβ peptide can also decrease AD‐relevant hippocampal markers of pathology. 198 These experimental findings strengthen evidence for a causative link between premorbid physical inactivity and dementia, but further work from a “reverse translation” perspective is required to illuminate factors which may account for the inconsistent effects observed in human intervention studies and, if appropriate, suggest optimal timing, duration and intensity for future clinical interventions.…”

Physical exercise regulates microglia in health and disease

“…In terms of specific microglial parameters, conflicting evidence exists regarding the impact of exercise on microglial numbers in AD mice. Some studies suggest that exercise leads to a decrease in microglial numbers ( Ke et al, 2011 ; Leem et al, 2011 ; Rodríguez et al, 2015 ; Wang Y. et al, 2023 ; Yang et al, 2023 ), while others indicate an increase ( Elahi et al, 2016 ; Xu et al, 2016 ; Hashiguchi et al, 2020 ; Zhang S. et al, 2022 ; Campos et al, 2023 ), and some findings show no significant change in microglial density in AD mice ( Xu et al, 2018 ; Zhang J. et al, 2018 ; Ziegler-Waldkirch et al, 2018 ; Oroszi et al, 2023 ). In terms of microglial phenotype, exercise can regulate CD68+ ( Ziegler-Waldkirch et al, 2018 ; Zhang S. et al, 2022 ; Oroszi et al, 2023 ; Wang Y. et al, 2023 ), CD86+ ( Lu et al, 2017 ; Zhang et al, 2019 ; Feng et al, 2023 ; Yang et al, 2023 ), triggering receptor expressed on myeloid cells 2 (TREM2) ( Zhang L. et al, 2022 ) and inflammatory molecules ( Xu et al, 2016 , 2018 ; Nakanishi et al, 2021 ; Han et al, 2023 ) in AD rodent models.…”