Exercise Intervention for Alzheimer’s Disease: Unraveling Neurobiological Mechanisms and Assessing Effects
Abstract
:1. Introduction
2. Exercise Regulates Bone-Derived Factors to Improve Symptoms of Alzheimer’s Disease through “Bone–Brain Crosstalk”
- OCN produced by osteoblasts enhances the synthesis and secretion levels of monoamine neurotransmitters (MN) while inhibiting the secretion and synthesis of γ-aminobutyric acid (GABA) [27], thereby improving learning, memory, and brain metabolic function. OCN also increases the secretion of brain-derived neurotrophic factor (BDNF), which subsequently improves the impact on neurodevelopment and function, reduces inflammatory responses, inhibits cell apoptosis, and suppresses anxiety and depressive behaviors. Exercise-induced skeletal stimulation can regulate OCN secretion levels, allowing it to accumulate in the brainstem, thalamus, and hypothalamus through the blood–brain barrier [28]. It binds specifically to neurons in the brain, influencing neurotransmitter synthesis and signal transmission. OCN further promotes the organism’s learning and memory abilities, increases neurotransmitter synthesis, and improves hippocampal development, thus enhancing cognitive function and inhibiting the development of anxiety emotions [29]. Additionally, OCN directly prevents neuronal apoptosis in the hippocampus, thereby protecting cognitive functions such as spatial learning and memory [30]. The binding of OCN and Gpr158 in CA3 pyramidal neurons of the hippocampus enhances the synthesis and secretion of neurotransmitters such as 5-hydroxytryptamine (5-HT), dopamine (DA), and norepinephrine (NE), while inhibiting GABA synthesis, thereby improving spatial learning and memory abilities [31]. The total osteocalcin (tOCN) content in the body primarily consists of carboxylated osteocalcin (cOCN) and undercarboxylated osteocalcin (uOCN), which is biologically active. Exercise stimulation can increase the overall activity level of uOCN. Additionally, exercise promotes the production of active uOCN by increasing muscle secretion of interleukin-6 (IL-6) [32,33]. Higher circulating OCN levels can significantly regulate the prevention of age-related cognitive decline. Exercise improves skeletal secretion capacity, increases circulating OCN levels in the body, and induces neuronal plasticity. Improved cognitive function can be achieved through OCN signaling [34,35,36,37].
- The SOST, synthesized by osteocytes, binds to LDH receptor-related proteins 4/5/6 (Lrp4/5/6) to antagonize the Wnt/β-catenin signaling pathway. Intracerebral Wnt/β-catenin signaling is involved in maintaining neurogenesis, synaptic plasticity, and blood–brain barrier integrity. Wnt/β-catenin signaling regulates synaptic plasticity, and memory processes, inhibits neurotoxicity caused by Aβ, and participates in tau protein phosphorylation and learning and memory. Dysfunction of Wnt/β-catenin can lead to the production and aggregation of Aβ, thereby triggering the onset of AD [38,39]. Wnt/β-catenin signaling is considered a potential mechanism for treating AD. Among the mechanisms that affect brain Wnt/β-catenin signaling, Dickkopf-related protein 1 (Dkk1) can inhibit Wnt signaling by inducing LRP5/6, thereby blocking the Wnt signal-induced synaptic disassembly process [40]. Dkk1 is overexpressed in AD patients and in the brains of AD mice, and its expression levels can be effectively reduced through exercise [41]. Exercise stimulation activates the Wnt signaling pathway in APP/PS1 rats, improving synaptic dysfunction and promoting synaptic plasticity and neurogenesis in the hippocampus [42,43]. In the brain mechanism, Aβ activates glycogen synthase kinase-3β (GSK-3β) and reduces β-catenin activity, blocking the Wnt/β-catenin signaling pathway. Exercise attenuates the secretion of SOST from the bone, thereby effectively improving the occurrence and development of AD through the Wnt/β-catenin pathway. Research has found that the expression levels of SOST significantly decrease in 8-week-old mice after 5 weeks of exercise. In human studies, both highly active males and females exhibit lower levels of SOST secretion and circulation [44]. Exercise activates Wnt/β-catenin signaling in the brain, leading to an increase in β-catenin levels within brain cells, which tends to stabilize. Rats subjected to treadmill exercise for 30 min/day, 5 days/week, for a total of 12 weeks, show increased expression levels of Wnt3, reduced expression of GSK-3β, activation of the Wnt signaling pathway, increased neurogenesis, and alleviated memory loss associated with AD [45]. After exercise, the secretion of SOST from the bone decreases, resulting in a reduced amount circulating through the blood–brain barrier. This reduction weakens its binding with Lrp4/5/6, further activating the Wnt/β-catenin signaling pathway, ultimately promoting synaptic plasticity and neurogenesis, and mitigating AD levels and biological mechanisms [46].
- OPN is a matrix cell immune regulator highly expressed by monocytes in the bone marrow, and it can regulate immune cell migration while responding to brain injuries [47]. Compared to chronic patients, AD patients have higher levels of OPN protein in their cerebrospinal fluid and plasma, suggesting that OPN plays a role in protecting neurons regulating brain diseases, and repairing neurodegenerative diseases [41]. OPN is involved in the process of brain remodeling, promoting myelination formation and regeneration [48]. Moderate-intensity (85% VO2 max) treadmill and weight-bearing running interventions for 5 weeks in 2-month-old male C57BL/6 mice can improve mouse bone mineral density (BMD), cortical bone mass, and osteogenic ability, as well as increase the expression and secretion levels of OCN and OPN in osteoblasts [49,50]. OPN enters the brain through the blood–brain barrier for regulation. OPN is mainly involved in AD neuron loss, degeneration, and the death of neurons. It plays a role in AD neuron abnormalities and re-entry into the cell cycle and/or myelin regenerative processes [51]. Studies have found that the increased expression of OPN is closely related to Aβ deposition in the cone neurons of AD patients and the brains of APP/PS1 mice [52]. In the process of OPN regulating AD, OPN binds to downstream receptor CD44 to further exert neuroprotective and remodeling activities. Due to the important role of the OPN–CD44 complex in neuroprotection and remodeling, enhancing OPN expression can inhibit neuro-damaging phenomena in AD [53,54]. Exercise stimulates OPN secretion and increases its expression levels in the bone. Strengthening OPN expression can better inhibit neuro damage in AD. In the Aβ clearance mechanism of AD, OPN can also regulate macrophage immune resistance to Aβ deposition. OPN promotes the phagocytosis of Aβ fibrils and related receptors, changes cell morphology, reduces inducible nitric oxide synthase (iNOS) levels, and enhances the anti-inflammatory effects of interleukin-10(IL-10) and matrix metalloproteinase 9 (MMP-9) [47] (Figure 1).
3. Exercise-Induced Modulation of Muscle Factors Improves Alzheimer’s Disease Symptoms through “Muscle–Brain Crosstalk”
- BDNF, a neurotrophic factor, plays a crucial role in neurogenesis and synaptic plasticity. Its low levels are linked to AD, with studies indicating reduced BDNF in AD patients and animal models [55,56,57]. BDNF can cross the blood–brain barrier, enhancing neurotrophic production in the hippocampus and supporting cognitive function [58,59]. Exercise has been shown to increase BDNF secretion in muscle tissue, correlating with exercise intensity and leading to cognitive improvements in both humans and animal models of AD [60,61,62]. Long-term exercise can elevate baseline BDNF levels, with evidence of hippocampal growth and better spatial memory after a year of aerobic exercise [63,64]. BDNF acts through the TrkB receptor, activating pathways like MAPK and PI3K, which are important for neuronal survival and plasticity [65]. It also modulates amyloid-beta (Aβ) production by enhancing alpha-secretase activity and reducing BACE1 levels, mitigating Aβ-induced toxicity [66,67,68,69,70]. Thus, exercise-induced BDNF not only offers direct neuroprotective effects but may also contribute to the reduction in AD pathology. These findings illustrate that BDNF plays a dual role in maintaining brain health and combating AD. By promoting neurogenesis and modulating pathological processes associated with AD, BDNF emerges as a promising therapeutic target. The research underscores the importance of long-term exercise, not only for its direct elevation of BDNF levels but also for its potential benefits in cognitive enhancement and the deceleration of AD pathology. Future studies may focus on how to maximize the impact of exercise on BDNF and how to translate these findings into concrete preventative and therapeutic strategies.
- Irisin, a myokine released during exercise, is produced by the cleavage of FNDC5 and affects energy metabolism and neuroprotection [71]. It promotes the browning of white adipose tissue, enhances insulin sensitivity, and is implicated in the pathophysiology of AD, with lower levels observed in AD models [62,72,73]. Exercise activates PGC-1α, up-regulating FNDC5/Irisin and reducing amyloid-beta (Aβ) production [74,75]. Irisin levels rise in response to exercise, potentially improving cognitive functions via various mechanisms, including promoting neuronal growth and reducing inflammation [76,77,78,79,80,81,82,83,84,85,86,87,88,89]. Irisin also influences the production of BDNF, a factor crucial for neuronal health [90,91,92]. Considering AD’s metabolic aspects, often termed “type 3 diabetes,” Irisin’s role in energy homeostasis and insulin sensitivity is of particular interest, offering a potential therapeutic avenue for AD and diabetes [93,94,95,96]. In summary, Irisin emerges as a promising molecule linking exercise to metabolic and cognitive health. Its multifaceted role in energy regulation, neuroprotection, and potential to mitigate AD symptoms underscores the need for further research. Future studies should focus on the therapeutic potential of Irisin, aiming to harness its benefits for treating metabolic and neurodegenerative disorders in aging populations.
- IL-6, a cytokine released from muscles during exercise, plays complex roles in the body and is linked to AD. High baseline levels of IL-6 are associated with increased risk of AD and cognitive decline in the elderly [97,98,99,100,101]. This cytokine has dual effects in AD: it can exacerbate neuronal damage by enhancing APP synthesis and Aβ toxicity, yet it also supports neurogenesis and gliogenesis through specific signaling pathways [102,103,104]. Acute exercise raises IL-6 levels, which may help regulate inflammation and promote neuroprotective responses [105,106]. Chronic exercise, conversely, is associated with reduced resting IL-6 levels and may prevent its detrimental effects in the brain [107,108,109]. In essence, while acute exercise triggers a beneficial IL-6 response that protects the brain, chronic exercise lowers the baseline of IL-6, potentially reducing chronic inflammation and the risk of neurodegenerative diseases. This suggests that exercise, both acute and chronic, can be a strategic approach to modulate IL-6 levels for brain health, emphasizing the importance of physical activity in the prevention and management of AD.
- IGF-1 plays a crucial role in CNS function by enhancing synaptic plasticity and density, with a decline in IGF-1 associated with AD cognitive symptoms [110,111]. Exercise-induced IGF-1 secretion from muscles benefits brain health, potentially reducing AD pathology through mechanisms like inhibiting Aβ production and tau phosphorylation via the IRS1/PI3K/Akt/mTOR pathway [112]. It also supports hippocampal neurogenesis and BDNF regulation, integral to neuronal growth and differentiation [113,114,115]. Similarly, VEGF, a key angiogenesis regulator, promotes vascular and neural health. Its overexpression in rodent models boosts hippocampal angiogenesis and neurogenesis, while its inhibition can negate exercise-induced neurogenic benefits, highlighting the importance of muscle–brain crosstalk [116,117,118,119]. These studies highlight how exercise promotes brain health by stimulating the secretion of molecules such as IGF-1 and VEGF, particularly with respect to neuroprotection and neurogenesis associated with AD. These findings reveal the biochemical links between physical activity and brain health, offering potential strategies for the prevention and treatment of AD. By enhancing the health of the vascular and nervous systems, exercise not only aids in improving cognitive functions but may also slow the progression of AD (Figure 1).
4. Exercise Regulates the Gut Microbiota and Improves Symptoms of Alzheimer’s Disease through “Gut–Brain Crosstalk”
5. Effects of Different Exercise Intervention Programs on Symptom Improvement in Alzheimer’s Disease
5.1. Effects of Different Types of Exercise on Symptom Improvement in Alzheimer’s Disease
5.1.1. Aerobic Exercise
5.1.2. Resistance Exercise
5.1.3. Multimodal Exercises Combination
5.2. Effects of Different Exercise Intensities and Frequencies on Symptom Improvement in Alzheimer’s Disease
5.3. Characteristics and Risk of Bias in Exercise Intervention Studies for Alzheimer’s Disease
6. The Role of Artificial Intelligence and Neuroimaging Technologies in Exercise Intervention for Alzheimer’s Disease
7. Discussion
8. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Author (s) | Exercise Type | Intensity | Frequency | Outcomes |
---|---|---|---|---|
Friedman, R. et al., 1991 [153] | walking | Low | 3 times/week × 30 min × 10 weeks | communication performance improved |
Venturelli, M. et al., 2011 [154] | walking | Moderate | 4 times/week × 30 min × 24 weeks | stabilize the progressive cognitive dysfunctions |
Arcoverde, C. et al., 2014 [155] | treadmill | Moderate | 2 times/week × 30 min × 16 weeks | improvement in the functional capacity |
McCurry, S.M. et al., 2011 [157] | walking | unclear | 3 times/week × 6 months | improving sleep |
Yang, S.Y. et al., 2015 [158] | cycling | Moderate | 3 times/week × 40 min × 3 months | improve cognitive function |
Hoffmann, K. et al., 2015 [160] | strength, cycling | Moderate-to-high | 3 times/week × 60 min × 16 weeks | reduced neuropsychiatric symptoms |
Yu, F. et al., 2021 [161] | cycling | Moderate-to-high | 3 times/week × 20–50 min × 6 months | reduce decline in global cognition |
Ahn, N. et al., 2015 [163] | resistance exercise | unclear | 3 times/week × 5 months | improved muscle strength and endurance, cardiovascular function, and gait speed |
Ben, A.I. et al., 2021 [164] | cycling, cognitive games | Moderate | Acute Exercise | improve cognitive functions |
Sampaio, A. et al., 2019 [165] | Multicomponent Training | unclear | 2 times/week × 45–55 min × 6 months | improve physical and cognitive functions |
Rolland, Y. et al., 2007 [166] | Collective exercise program | Low | 2 times/week × 60 min × 12 months | significantly slower decline in ADL score |
Sanders, L. et al., 2020 [167] | walking and lower limb strength training | Low and high | 3 times/week × 60 min × 24 weeks | no beneficial effects of the exercise vs. control group on cognitive function. |
Toots, A. et al., 2017 [168] | Functional Exercise program | High | 5 times/2 week × 45 min × 4 months | no superior effects on global cognition or executive function |
Author (s) | Study Design | Sample Size | Statistical Method | Consistency of Results | Risk of Bias |
---|---|---|---|---|---|
Friedman, R. et al., 1991 [153] | Randomized, non-blinded two-group experimental | 30 | MANOVA | High | Medium |
Venturelli, M. et al., 2011 [154] | Randomized controlled trial | 21 | ANOVA | High | Medium |
Arcoverde, C. et al., 2014 [155] | Randomized controlled trial | 20 | independent sample t-test | High | Medium |
McCurry, S.M. et al., 2011 [157] | Randomized, controlled trial with blinded assessors | 132 | unclear | High | Unclear |
Yang, S.Y. et al., 2015 [158] | Randomized controlled trial | 50 | paired samples t-test | High | Low |
Hoffmann, K. et al., 2015 [160] | Randomized controlled trial | 200 | linear regression models using generalized estimating equations | High | Low |
Yu, F. et al., 2021 [161] | Randomized controlled trial | 96 | 2-sided t-test | High | Low |
Ahn, N. et al., 2015 [163] | Randomized controlled trial | 23 | unclear | High | Unclear |
Ben, A.I. et al., 2021 [164] | Randomized controlled trial | 79 | ANOVA | High | Low |
Sampaio, A. et al., 2019 [165] | Non-randomized study | 37 | ANOVA | High | Medium |
Rolland, Y. et al., 2007 [166] | Randomized controlled trial | 134 | Multiple logistic regression analyses | High | Low |
Sanders, L. et al., 2020 [167] | Randomized controlled trial | 91 | ANCOVA | Low | Medium |
Toots, A. et al., 2017 [168] | Randomized controlled trial | 186 | Linear mixed models | Low | Medium |
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Ren, J.; Xiao, H. Exercise Intervention for Alzheimer’s Disease: Unraveling Neurobiological Mechanisms and Assessing Effects. Life 2023, 13, 2285. https://doi.org/10.3390/life13122285
Ren J, Xiao H. Exercise Intervention for Alzheimer’s Disease: Unraveling Neurobiological Mechanisms and Assessing Effects. Life. 2023; 13(12):2285. https://doi.org/10.3390/life13122285
Chicago/Turabian StyleRen, Jianchang, and Haili Xiao. 2023. "Exercise Intervention for Alzheimer’s Disease: Unraveling Neurobiological Mechanisms and Assessing Effects" Life 13, no. 12: 2285. https://doi.org/10.3390/life13122285