The Effects of Physical Running on Dendritic Spines and Amyloid-beta Pathology in 3xTg-AD Male Mice

Abstract

Memory loss is the key symptom of Alzheimer's disease (AD). As successful drug treatments have not yet been identified, non-pharmaceutical interventions such as physical exercise and training have been employed to improve the memory function of people with dementia. We investigated the effect of prolonged physical running on hippocampal-dependent spatial memory and its underlying mechanisms using a well-established rodent model of AD. 3xTg-AD transgenic mice and non-transgenic mice were subjected to voluntary wheel running for 5 months (1 hour per day, 5 days per week), followed by spatial memory testing. After the behavioral testing, dendritic spines, synapses, and synaptic proteins as well as amyloid-beta (Aβ) pathology were analyzed in the dorsal hippocampi. Running improved hippocampal-dependent spatial memory in 3xTg-AD mice. This running strategy prevented both thin and mushroom-type spines on CA1 pyramidal cells in 3xTg-AD mice, whereas the effects of running in non-transgenic mice were limited to thin spines. The enormous effects of running on spines were accompanied by an increased number of synapses and upregulated expression of synaptic proteins. Notably, running downregulated the processing of amyloid precursor protein, decreasing intracellular APP expression and extracellular Aβ accumulation, and spatial memory performance correlated with levels of Aβ peptides Aβ 1-40 and Aβ 1-42 . These data suggest that prolonged running may improve memory in preclinical AD via slowing down the amyloid pathology and preventing the loss of synaptic contacts.

Effect of exercise on cognitive function and synaptic plasticity in Alzheimer's disease models: A systematic review and meta-analysis

“…After reviewing the full texts, 62 studies were excluded for the following reasons: nine for animals that were not models of AD; five for no exercise as an isolated intervention; one for no long-term exercise; 47 for no assessments or reports of results related to MWM or synaptic plasticity. In the end, 20 studies met the inclusion criteria and were included in the qualitative analysis (Wang et al, 2013 , 2021 ; Kim et al, 2014 ; Revilla et al, 2014 ; Cho et al, 2015 ; Dao et al, 2015 , 2016 ; Zhao et al, 2015 , 2020 ; Wu et al, 2018 ; Lourenco et al, 2019 ; Belaya et al, 2020 ; Liu et al, 2020 , 2022 ; Li et al, 2021 , 2022 ; Mu et al, 2022 ; Park et al, 2022 ; Xu et al, 2022 ; Yang et al, 2022 ). Twelve for the quantitative analysis because of the lacked data on synaptic plasticity of the eight articles (Revilla et al, 2014 ; Cho et al, 2015 ; Belaya et al, 2020 ; Liu et al, 2020 , 2022 ; Zhao et al, 2020 ; Li et al, 2021 , 2022 ; Wang et al, 2021 ; Mu et al, 2022 ; Park et al, 2022 ; Xu et al, 2022 ).…”

“…In the end, 20 studies met the inclusion criteria and were included in the qualitative analysis (Wang et al, 2013 , 2021 ; Kim et al, 2014 ; Revilla et al, 2014 ; Cho et al, 2015 ; Dao et al, 2015 , 2016 ; Zhao et al, 2015 , 2020 ; Wu et al, 2018 ; Lourenco et al, 2019 ; Belaya et al, 2020 ; Liu et al, 2020 , 2022 ; Li et al, 2021 , 2022 ; Mu et al, 2022 ; Park et al, 2022 ; Xu et al, 2022 ; Yang et al, 2022 ). Twelve for the quantitative analysis because of the lacked data on synaptic plasticity of the eight articles (Revilla et al, 2014 ; Cho et al, 2015 ; Belaya et al, 2020 ; Liu et al, 2020 , 2022 ; Zhao et al, 2020 ; Li et al, 2021 , 2022 ; Wang et al, 2021 ; Mu et al, 2022 ; Park et al, 2022 ; Xu et al, 2022 ). The flow diagram of the selection process is shown in Figure 1 .…”

“…Since three studies (Cho et al, 2015 ; Wang et al, 2021 ; Liu et al, 2022 ) performed RCTs for exercise intervention before and after AD, finally, 11 RCTs from eight studies (Cho et al, 2015 ; Zhao et al, 2020 ; Li et al, 2021 , 2022 ; Wang et al, 2021 ; Liu et al, 2022 ; Park et al, 2022 ; Xu et al, 2022 ) including 240 animals reported the impact of exercise on decreasing escape latency compared with the control group. The results demonstrated that the exercise group had a significant effect on decreasing escape latency compared with the control group (SMD = −0.86, 95% CI: −1.21 to −0.50, P < 0.001).…”

“…. E ect of exercise on synaptic plasticity in AD models: Dendritic spine density Totally, three studies (Mu et al, 2022;Xu et al, 2022;Yang et al, 2022) have reported an association between a higher density of dendritic spines and exercise. Dendritic spines are small projections on the dendrite stem that form synapses with the axons of neurons to receive and integrate information (Chidambaram et al, 2019), which are highly correlated with hippocampus-dependent spatial navigation (Bolding et al, 2019).…”

“…The results displayed that the dendritic spine density of the hippocampus was obviously higher in the exercise group than the sedentary controls. Furthermore, two studies (Mu et al, 2022;Xu et al, 2022) reported in detail that exercise pretreatment blocked the decrease in the number of thin spines, mushroom spines, and stubby spines both in the hippocampus and prefrontal cortex. In the study by (Mu et al, 2022), there was also reported that treadmill exercise enhanced the axon length and dendritic complexity.…”