Combined effects of aerobic exercise and 40-Hz light flicker exposure on early cognitive impairments in Alzheimer’s disease of 3×Tg mice

Abstract

Alzheimer's disease (AD) is a progressive degenerative brain disease and the primary cause of dementia. At an early stage, AD is generally characterized by short-term memory impairment, owing to dysfunctions of the cortex and hippocampus. We previously reported that a combination of exercise and 40 Hz light flickering can protect against AD-related neuroinflammation, gamma oscillations, reduction in Aβ, and cognitive decline. Therefore, we sought to extend our previous findings to the 5-month-old 3xTg-AD mouse model to examine whether the same favorable effects occur in earlier stages of cognitive dysfunction. We investigated the effects of 12 weeks of exercise combined with 40-Hz light flickering on cognitive function by analyzing neuroinflammation, mitochondrial function, and neuroplasticity in the hippocampus in a 3xTg-AD mouse model. 5-month-old 3xTg-AD mice performed 12 weeks of exercise with 40-Hz light flickering administered independently and in combination. Spatial learning and memory, long-term memory, hippocampal Aβ, tau, neuroinflammation, pro-inflammatory cytokine expression, mitochondrial function, and neuroplasticity, were analyzed. Aβ and tau proteins levels were significantly reduced in the early stage of AD, resulting in protection against cognitive decline by reducing neuroinflammation and pro-inflammatory cytokines. Furthermore, mitochondrial function improved, apoptosis was reduced, and synapse-related protein expression increased. Overall, exercise with 40-Hz light flickering was significantly more effective than exercise or 40-Hz light flickering alone, and the improvement was comparable to the levels in the non-transgenic aged-match control group. Our results indicate a synergistic effect of exercise and 40-Hz light flickering on pathological improvements in the hippocampus during early AD associated cognitive impairment.

Neuropsychological and Neurophysiological Mechanisms behind Flickering Light Stimulus Processing

“…Critical flicker fusion frequency (CFF or CFFF), as a frequency at which flickering light stops being visible and starts being perceived as a steady light, has been used in various fields of research and various groups or species. Research has focused on dementia [ 1 , 2 , 3 ], visual impairment [ 4 ], cognitive functioning [ 5 , 6 , 7 , 8 ] and divers [ 9 , 10 , 11 , 12 , 13 , 14 ], among other topics.…”

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).…”

“…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, 10 RCTs from seven studies (Cho et al, 2015 ; Zhao et al, 2020 ; Wang et al, 2021 ; Li et al, 2022 ; Liu et al, 2022 ; Park et al, 2022 ; Xu et al, 2022 ) including 210 animals adopted time in the target quadrant as an outcome indicator. The results of the meta-analysis displayed that the exercise group had a significant effect on increasing time in the target quadrant, compared with the control group (SMD = 1.65, 95% CI: 0.95–2.36, P < 0.…”