Weizhe Zhen
Yanfeng Xing2
Hongjun Zhen- 1Graduate School, Capital Medical University, Beijing, China
- 2Department of Orthopedics, Handan Chinese Medicine Hospital, Handan, Hebei, China
During the processing and assembly of β-amyloid precursor protein (APP), the amyloidogenic pathway represents a crucial component of Alzheimer’s disease (AD) pathogenesis. The non-amyloidogenic pathway does not generate toxic Aβ. For a long time, research has delved deeply into both pathways, elucidating numerous important details and mechanisms within these processes. Scientists and clinicians have sought to design effective therapeutic interventions based on these mechanisms. However, this endeavor has encountered numerous setbacks, resulting in no currently available drugs capable of reversing AD progression. Regarding APP processing and assembly, we are curious whether daily activities influence these processes. We focus on exercise as a daily activity, systematically exploring whether it affects APP processing and assembly and the underlying mechanisms. Furthermore, we examine alterations in APP processing and assembly in exercise-related injury disorders, summarizing and analyzing existing research. We discuss promising future research directions, aiming to contribute to preventing adverse outcomes following exercise-related injuries.
Introduction
Extracellular neuroinflammatory plaques composed of β-amyloid (Aβ) are one of the primary pathological manifestations of Alzheimer’s disease(AD) (Zheng and Wang, 2025). Although currently available treatments for AD are limited, some therapeutic approaches aim to exert their effects by clearing Aβ plaques. As basic research continues to advance, Aβ has increasingly been found to be closely associated with numerous other diseases and pathological changes (Stein et al., 2015; Jang et al., 2022). This has also driven research to focus on the formation and aggregation processes of Aβ plaques. Aβ is generated through the proteolytic processing of the β-amyloid precursor protein (APP). Abnormalities in this process are widely recognized as one of the primary causes of AD.
Exercise is an indispensable part of human life. Many people maintain regular exercise habits, and even those without structured exercise plans still achieve a certain amount of physical activity through commuting, shopping, and other daily routines. Whether exercise influences the APP assembly process remains inconclusive, as current research lacks sufficient evidence to reach a universally accepted conclusion. Nevertheless, this represents a highly significant avenue for further investigation. Gaining deeper insights into how different types of exercise, varying in frequency, duration, and intensity, affect the APP assembly process over sustained periods could profoundly and positively impact our ability to provide daily exercise recommendations for individuals with Aβ-related diseases. It may even pave the way for developing novel physical therapies.
Exercise can be categorized into aerobic and anaerobic activities. For anaerobic exercise, the rapid bursts of short-term strength exertion make beginners or those without proper warm-ups highly susceptible to sports injuries. Even with aerobic exercise, prolonged strenuous activity and improper muscle relaxation techniques can lead to joint and muscle strain, or even skeletal damage, among participants. While we aim to prevent sports injuries, they remain an inherent and frequent occurrence in athletic activities. During the injury process and subsequent disease progression, whether APP undergoes abnormal hydrolysis, assembly, or modification, and whether Aβ plaques form and aggregate abnormally, remains unknown—yet constitutes a highly intriguing research question.
β-amyloid precursor protein and its assembly process
β-amyloid precursor protein is a type I transmembrane protein that forms the mammalian APP family alongside APP-like proteins amyloid beta precursor like protein 1 (APLP1) and proteins amyloid beta precursor like protein 2 (APLP2). Biological functions involving APP family members include nervous system development, formation and function of the neuromuscular junction, synaptogenesis, dendritic complexity and spine density, axonal growth and guidance, and synaptic function—including synaptic plasticity, learning, and memory (Müller et al., 2017). APP primarily follows two metabolic pathways: the non-amyloidogenic pathway and the amyloidogenic pathway. The amyloidogenic pathway produces β-Amyloid (Aβ), whose resulting plaques constitute one of the hallmark pathological features of AD. Which pathway APP follows for metabolism depends on the enzyme involved in the first cleavage step. When α-secretase is involved in the first cleavage, the integrity of the Aβ peptide segment is disrupted, thereby preventing the generation of full-length Aβ (Lichtenthaler and Haass, 2004). When β-secretase participates in the first cleavage step, the process of Aβ generation is initiated (Vassar et al., 1999). β-secretase is a key enzyme regulating APP metabolism, working in concert with γ-secretase which performs the second cleavage step to generate Aβ fragments. Its abnormal activation leads to an imbalance in the Aβ42/Aβ40 ratio (Citron, 2002). Gamma-secretase is a multimeric aspartic protease that cleaves the transmembrane region of the β-carboxy-terminal fragment (βCTF) derived from APP, ultimately yielding a series of Aβ peptides of varying lengths (Tomita, 2008; Yonemura et al., 2011; Funamoto et al., 2020). Research on APP has largely been concentrated over the past two decades, with its physiological functions, specificity, and transmembrane domains continually being elucidated (Ashall and Goate, 1994; Tischer and Cordell, 1996). In recent years, research on APP has increasingly focused on them as a breakthrough in clinical therapies. Although no proven effective treatments have been approved yet, multiple novel drugs are being developed and entering clinical trials during the research phase (Koriyama et al., 2021). As novel research techniques are developed, they are also employed as characteristic markers in the construction of cellular models (Tunesi et al., 2020).
The role and mechanism of APP in the course of AD
β-amyloid precursor protein plays a significant role throughout the entire disease progression of AD and can even be considered one of the key initiators (Chen et al., 2024). Its primary function lies in serving as the source within the “amyloid cascade hypothesis.” Factors such as polygenic mutations alter the process by which APP generates Aβ, leading to increased production of Aβ42, which in turn promotes Aβ deposition (Hardy and Higgins, 1992). However, this does not mark the end of APP’s role in the AD process. As research deepens, Aβ-forming plaques are no longer universally recognized as the primary mechanism of AD pathogenesis, and other mechanisms are gradually gaining acceptance. Among these, Aβ oligomers have emerged as a focal point of intense attention. APP metabolism can generate Aβ oligomers, which not only inhibit long-term potentiation (LTP) and enhance long-term depression (LTD), but can also cause damage to synaptic structures (Selkoe, 2008). Beyond their effects on synapses, Aβ oligomers can also exert neurotoxicity and trigger multifaceted destructive effects such as neuroinflammation (Heneka et al., 2015; Sui et al., 2015). These effects initiated by the APP interact with one another, collectively driving the progression of AD.
The modulating effect of exercise on the course of Alzheimer’s disease
Physical activity is integral to daily life. Even when we don’t set aside dedicated time for exercise, routine commutes and daily activities often provide a certain level of movement without us realizing it. A growing body of research indicates that exercise can effectively slow cognitive decline in elderly patients with mild to moderate AD (Yu et al., 2021), demonstrating significant potential as a preventive and even therapeutic strategy. There are numerous classification criteria for exercise, such as categorizing it into aerobic and anaerobic activities. Previous studies have focused on whether both aerobic and anaerobic exercise exert beneficial effects on cognitive function and pathological manifestations in AD patients (Table 1). Aerobic exercise is defined as sustained rhythmic activity involving large muscle groups, where oxygen demand does not exceed oxygen supply. Anaerobic exercise encompasses brief, intense activities such as weightlifting, sprinting, and high-intensity interval training, where oxygen demand exceeds oxygen supply (Huang et al., 2023). Resistance training also largely falls under the category of anaerobic exercise (Smith et al., 2019). Based on the research findings, both types of exercise can exert beneficial effects (Alkadhi and Dao, 2018; Liu et al., 2020; Rossi Daré et al., 2020; Gaitán et al., 2021; Zhou et al., 2022; Azevedo et al., 2023; Cui et al., 2023; Sepúlveda-Lara et al., 2024; Liang et al., 2025). In contrast, aerobic exercise has garnered greater research attention, with several randomized controlled trials designed and completed to investigate its effects on AD (Morris et al., 2017). Similarly, exercise duration and intensity are variables of significant interest to researchers. While high-intensity and moderate-intensity exercise do not alter the expression of AD-related genes in cognitively unimpaired older adults, moderate-to-high-intensity exercise effectively alleviates neuropsychiatric symptoms in patients with mild AD (Hoffmann et al., 2016; Marston et al., 2024).
Table 1. The effects of different types of exercise and injury conditions on β-amyloid precursor protein (APP) processing, β-amyloid (Aβ) levels and cognitive outcomes.
The impact of exercise on the processing and assembly process of the APP
The impact of exercise on APP processing remains poorly understood, with insufficient research evidence elucidating the complete mechanisms underlying this process. This leaves significant uncharted territory for future exploration. Current studies directly revealing the mechanisms by which exercise influences APP processing suggest that exercise can downregulate β-site amyloid precursor protein-cleaving enzyme 1 mRNA (Yu et al., 2013). Although studies directly revealing the effects of exercise on APP processing changes are scarce, we can identify several potential mechanisms from other related research that warrant further clarification. These mechanisms often feature key biomolecules as their core components (Figures 1, 2).
Figure 1. The interaction between key biomolecules. PTGS2, prostaglandin-endoperoxide synthase 2, also known as cyclooxygenase 2 (COX2); MAPK1, mitogen-activated protein kinase 1, also known as extracellular signal-regulated kinase (ERK); CREB1, CAMP response element-binding protein 1; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; CTSB, cathepsins B; CTSD, cathepsins D; CTSE, cathepsins E; BACE1, APP-cleaving enzyme 1. *Draw by String: https://cn.string-db.org/.
Figure 2. The Key molecular pathways through which exercise influences β-amyloid precursor protein (APP) processing.
COX-2
Cyclooxygenase (COX) plays a key role in the synthesis of prostaglandin E2 (PGE2) from arachidonic acid (Zhu et al., 2025). COX has three isoforms: COX-1, COX-2, and COX-3. COX-2 is a potent enzyme that, upon stimulation by various inflammatory factors such as cytokines and bacteria, can trigger inflammation and promote prostaglandin synthesis (Yang et al., 2020). Its elevated levels are closely associated with the onset of AD (Moussa and Dayoub, 2023). Research indicates that its dysregulation may lead to abnormal cleavage of the APP (Qin et al., 2003; Guan and Wang, 2019), even creating a vicious cycle (Quadros et al., 2003). Exercise can inhibit the COX-2 pro-inflammatory pathway. Studies indicate that exercise significantly reduces COX-2 activity, potentially exerting therapeutic effects on vestibular migraine by suppressing COX-2-mediated inflammation (Lee et al., 2015). Moreover, moderate-intensity exercise can also reduce levels of COX-2 and APP (Pahlavani, 2023). This provides a theoretical basis for the potential therapeutic effect of exercise on AD by inhibiting COX-2, thereby preventing abnormal cleavage and the level of the APP. It also offers a direction for future research. Investigating whether exercise can indeed inhibit COX-2 in AD models, effectively prevent abnormal cleavage of APP, and reduce pathological products such as Aβ plaques may become a key focus for future research.
GAPDH
Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) has long been recognized as a crucial enzyme in energy metabolism, generating ATP and pyruvate through anaerobic glycolysis in the cytoplasm (Nicholls et al., 2012). Recent studies have progressively elucidated the crucial role of GAPDH in non-metabolic processes. Whether it is promoting the antitumor immune activity of CD8 T cells (Wang X. et al., 2024), acting as a housekeeping gene with oncogenic effects across various cancers (Wang J. et al., 2023), or participating in the heme maturation of myoglobin and hemoglobin, these findings reveal its significant biological importance beyond metabolic functions. In the pathogenesis of AD, GAPDH also plays a pivotal role (El Kadmiri et al., 2014). Research indicates that GAPDH can form high-affinity interactions with APP, which may be responsible for impaired glycolytic function in AD and could ultimately lead to cell death (El Kadmiri et al., 2014; Ahmad et al., 2023). However, limited research indicates that exercise can prevent the upregulation of GAPDH (Zhao et al., 2012). However, whether this mechanism can reduce the interaction between GAPDH and APP, thereby delaying the progression of AD, remains to be further investigated. Metabolism is a complex, multi-pathway biological process. To determine whether exercise can regulate APP by inhibiting GAPDH upregulation, it is necessary to observe whether GAPDH-APP interactions are weakened post-exercise, assess downstream GAPDH responses, and examine whether related metabolic processes like glycolysis regain function. Concurrently, monitoring changes in APP processing and assembly into Aβ is also essential.
BACE-1
β-amyloid precursor protein-cleaving enzyme 1 (BACE-1) is a novel type I transmembrane aspartic protease essential for the generation of Aβ peptides in AD (Venugopal et al., 2008; Singh et al., 2022a). BACE-1 is widely distributed throughout the central nervous system (CNS) and exhibits all functional characteristics of a β-secretase, acting as the key enzyme initiating Aβ formation (Luo et al., 2016) Increased neuronal BACE-1 activity is believed to promote the production of Aβ and the formation of amyloid plaques in the brains of AD patients (Singh et al., 2022b). BACE-1 cleaves the APP into soluble APP and the membrane-bound C-terminal fragment C99, a rate-limiting step. C99 is further cleaved by γ-secretase to produce Aβ (Gehlot et al., 2022). The beneficial effects of exercise on AD likely also stem from its regulation of BACE-1. Studies indicate that treadmill exercise (TE) prevents PS2 mutation-induced memory deficits and reduces Aβ-42 deposition by inhibiting β-secretase and its product C-99 in the cortex and/or hippocampus of aged PS2 mutant mice (Kang et al., 2013). This partially explains exercise’s inhibitory effect on BACE-1, indirectly suggesting that exercise may effectively regulate the processing changes of APP. However, current research evidence remains insufficient and requires further clarification and validation. For instance, experimental investigation into whether the non-amyloidogenic pathway is activated and experiments such as measuring APP content and APP gene transcription expression levels would enhance our understanding of the underlying mechanisms.
Cathepsins B, D, and E
Cathepsins are a class of proteases found within cells of various animal tissues and constitute major members of the cysteine protease family. Approximately 11 cathepsin isoforms are primarily present in the human body, with cathepsins B, D, E, and others having been demonstrated to be closely associated with AD pathogenesis. Cathepsins B, D, and E are all capable of metabolically degrading Aβ peptides. Among these, cathepsin D has been observed to cleave APP100-FLAG near the C-terminal end of the Aβ peptide. Meanwhile, cathepsin B exhibits high carboxypeptidase activity under low pH conditions. Therefore, the possibility that cathepsins D and B participate in the amyloid processing of APP cannot be ruled out (Mackay et al., 1997). Numerous studies have demonstrated that exercise can increase peripheral tissue protease B levels and improve cognitive function (Gökçe and Gün, 2023). However, whether cathepsins are involved in the process by which exercise improves cognitive function requires further research to elucidate.
ERK/CREB
Extracellular signal-regulated kinase (ERK) is a member of the mitogen-activated protein kinase (MAPK) family. CAMP response element-binding protein (CREB), which selectively binds to cAMP response elements (CRE) and regulates gene transcription in various cells, including dopaminergic neurons (Zhen et al., 2023). The ERK/CREB pathway has been increasingly elucidated to play a crucial role in the nervous system. Its function in mediating neurotrophic factors and exerting neuroprotective effects has been widely recognized (Grimes et al., 2015). ERK/CREB signaling regulates synaptic protein expression and learning and memory functions (Peng et al., 2010; Wang J. et al., 2023). The progression of AD is often accompanied by memory decline. A study on treadmill exercise has also demonstrated that it can effectively activate the ERK/CREB pathway (Seo et al., 2021). Although this study is limited to investigating signaling pathways and does not further clarify whether exercise can improve memory by activating the ERK/CREB pathway, it strongly suggests that exercise may enhance memory through this pathway. ERK is closely associated with APP, which was discovered long ago to potentially regulate ERK signaling (Venezia et al., 2006). Subsequent studies have further revealed that Ginsenoside Rg1 promotes non-amyloidgenic cleavage of APP via estrogen receptor signaling to MAPK/ERK (Shi et al., 2012). Additionally, studies have revealed that presenilin not only influences the processing of APP and the generation of Abeta, but also modulates the activity of the ERK through a protein kinase C alpha-dependent mechanism (Dehvari et al., 2008). This further adds to the complexity of the relationship between ERK and APP. Meanwhile, CREB has been found to exert transcriptional regulation over PEN-2, a key component of the γ-secretase complex (Wang et al., 2006). Not only ERK protein, but also the activation of the ERK/CREB pathway has been elucidated in studies as a crucial intermediate step in the non-amyloid cleavage and metabolism of APP (Guo et al., 2017). Therefore, exercise may exert potential therapeutic effects on AD by promoting the non-amyloid cleavage and processing of APP through effective activation of the ERK/CREB pathway. This warrants further investigation and validation by researchers in their studies.
APP assembly process and Aβ changes in exercise injury related diseases
Fracture
Fractures rank among the most common sports injuries. An intriguing question arises: Could sports-related fractures alter the assembly of APP, leading to abnormalities in learning, memory, and cognitive function and potentially even AD? This curiosity drives researchers and may concern fracture patients. While current research remains limited, existing studies offer some preliminary insights into this question, that it may affect cognitive function (Guo et al., 2014). Clinical studies directly reveal that among hip fracture patients without dementia, 88.6% of cognitively normal individuals exhibit partial or complete abnormalities in indicators such as the Aβ42/40 ratio, p-tau, and t-tau (Oh et al., 2018). Moreover, more in-depth research has focused on APP, revealing a potential shared molecular pathway in disease progression between femoral neck fractures, osteoporosis, and AD by investigating the close relationship between APP genes and bone remodeling genes such as TRAP and RANKL (Stapledon et al., 2021). Of course, current research has not revealed whether changes in the APP processing and assembly process occur during the injury itself or during the subsequent repair process. This research question presents numerous challenges awaiting breakthrough solutions. Among these, how to eliminate other influencing factors and determine whether fracture injury is one of the primary factors causing changes in APP assembly is a key issue requiring resolution. Additionally, the process of APP assembly changes as injury occurs and recovery progresses is a fascinating topic equally worthy of in-depth investigation.
Osteoporosis
Osteoporosis is a common disease that contributes to sports injuries. Previously, we often believed that this condition primarily affected the elderly or postmenopausal women (Johnston and Dagar, 2020; Walker and Shane, 2023). However, with the continuous evolution of lifestyle habits, osteoporosis has shown a trend toward younger onset, and the management of younger patients has become a difficult challenge to address (Herath et al., 2022; Ishimoto and Shah, 2024). We note that previous studies have found significantly elevated levels of Aβ in bone tissue affected by osteoporosis (Downey et al., 2017; Duan et al., 2023). Osteoporosis may also affect cognitive function (Zhao et al., 2023). This establishes a link between osteoporosis and Aβ, thereby paving the way for further investigation into the potential relationship between osteoporosis and AD (Wang H. S. et al., 2024; Nasme et al., 2025). However, this potential link remains uncertain unless elevated levels of Aβ are simultaneously detected in brain tissue from individuals with osteoporosis. This finding also suggests that osteoporosis may influence Aβ levels by affecting the assembly process of APP. While current research has not elucidated the underlying mechanisms, it points the way for future investigations.
Muscle injury
Muscle injuries rank among the most common conditions resulting from sports-related trauma. This category encompasses numerous distinct types of injuries. Among them, muscle strains are relatively more prevalent and generally easier to recover from. This group also includes more severe conditions like rhabdomyolysis, which can cause multi-organ involvement. Many such cases involve irreversible damage and tend to have a relatively slow recovery process (Guerrero-Hue et al., 2023; Nathan, 2023). Research indicates that muscle strains may lead to cognitive impairment (Guéniot et al., 2020). The connection between muscle mass and Aβ is strong. From a clinical research perspective, greater thigh muscle mass is associated with a lower risk of Aβ positivity in women (Kang et al., 2022). From a basic research perspective, intracellular accumulation of Aβ leads to Ca2+ dysregulation in skeletal muscle (Lopez and Shtifman, 2010). Moderate exercise can aid skeletal muscle energy metabolism, but inappropriate exercise may lead to certain traumatic injuries (Baumert et al., 2016; Yook and Cho, 2017). During this process, certain metabolic pathways may be disrupted. Recent research has focused intensely on the close association between exercise-induced myopathy and Aβ deposition. Findings suggest a potential strong link between severe exercise-induced myopathy and tissue infiltration by amyloid deposits in skeletal muscle (Appelman et al., 2024). APP, as the precursor of Aβ, is located at the base of the postsynaptic folds of the neuromuscular junction and is regulated by the neurotrophic factor neurotrophic factor-1 (NRG1). NRG1 causes a reduction in APP mRNA levels while simultaneously decreasing steady-state protein levels (Rosen et al., 2003). In skeletal muscle, the absence of NRG1 leads to the loss of neuromuscular synapses (Liu et al., 2019). Interestingly, NRG1 expression increases within the first 48 h after muscle injury, aiding in the remodeling and recovery of both presynaptic and postsynaptic regions (Pimentel Neto et al., 2025). This implies that during the initial phase of muscle injury, APP expression is likely influenced by increased NRG1 expression, resulting in a decrease in its levels. Whether APP levels rebound after 48 hours and whether Aβ deposition increases remains to be further investigated and discovered. For severe exercise-related muscle injury diseases such as rhabdomyolysis, the connection between these conditions and Aβ deposition represents an intriguing research direction; however, currently reported studies in this area remain limited.
The variety of diseases caused by exercise injuries is extensive, making it difficult to list them all in detail. Among these, some diseases may exhibit alterations in the APP processing pathway during their progression. Currently, most research on these diseases lacks findings that directly clarify the relationship between APP processing, Aβ generation and deposition, and disease progression. However, we can still discern a close connection between these diseases and cognitive impairment from a few studies, such as those on lumbar disk herniation (Luo et al., 2025). This underscores the value and significance of investigating mechanisms related to APP and Aβ (Figure 3).
Figure 3. The potential link between exercise-related injuries and alterations in β-amyloid precursor protein (APP) assembly and β-amyloid (Aβ) pathology.
Conclusion
Exercise is an integral part of everyone’s daily life. Currently, there is a lack of in-depth research evidence on whether the exercise process affects the processing and assembly of APP. However, this does not diminish the importance of studying this issue. It will help us gain a more comprehensive and profound understanding of exercise’s role in improving cognition and its impact on altering the progression of AD. Physical activity inevitably carries the risk of sports injuries. Regardless of their severity, such injuries may disrupt the processing and assembly of APP, potentially affecting cognition and even accelerating disease progression. Research in this direction holds equally significant value and importance. Clarifying whether sports injuries can impact cognition by affecting APP processing and assembly will help us avoid adverse outcomes.
Author contributions
WZ: Resources, Visualization, Funding acquisition, Formal analysis, Validation, Writing – original draft, Project administration, Investigation, Data curation, Supervision, Methodology, Writing – review & editing, Software, Conceptualization. YX: Investigation, Writing – original draft. YL: Investigation, Writing – original draft. JH: Investigation, Writing – original draft. LK: Writing – original draft, Investigation. HZ: Data curation, Supervision, Writing – original draft, Investigation, Software, Methodology, Writing – review & editing, Resources, Conceptualization, Visualization, Funding acquisition, Formal analysis, Validation, Project administration.
Funding
The author(s) declared that financial support was received for this work and/or its publication. This work was supported by Hebei Province Scientific Research Projects in Traditional Chinese Medicine (No. 2024193).
Conflict of interest
The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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The author(s) declared that generative AI was not used in the creation of this manuscript.
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References
Ahmad, I., Singh, R., Pal, S., Prajapati, S., Sachan, N., Laiq, Y., et al. (2023). Exploring the role of glycolytic enzymes PFKFB3 and GAPDH in the modulation of Aβ and neurodegeneration and their potential of therapeutic targets in Alzheimer’s Disease. Appl. Biochem. Biotechnol. 195, 4673–4688. doi: 10.1007/s12010-023-04340-0
Alkadhi, K. A., and Dao, A. T. (2018). Exercise decreases BACE and APP levels in the hippocampus of a rat model of Alzheimer’s disease. Mol. Cell Neurosci. 86, 25–29. doi: 10.1016/j.mcn.2017.11.008
Appelman, B., Charlton, B. T., Goulding, R. P., Kerkhoff, T. J., Breedveld, E. A., Noort, W., et al. (2024). Muscle abnormalities worsen after post-exertional malaise in long COVID. Nat. Commun. 15:17. doi: 10.1038/s41467-023-44432-3
Ashall, F., and Goate, A. M. (1994). Role of the beta-amyloid precursor protein in Alzheimer’s disease. Trends Biochem. Sci. 19, 42–46. doi: 10.1016/0968-0004(94)90173-2
Azevedo, C. V., Hashiguchi, D., Campos, H. C., Figueiredo, E. V., Otaviano, S. F. S. D., Penitente, A. R., et al. (2023). The effects of resistance exercise on cognitive function, amyloidogenesis, and neuroinflammation in Alzheimer’s disease. Front. Neurosci. 17:1131214. doi: 10.3389/fnins.2023.1131214
Baumert, P., Lake, M. J., Stewart, C. E., Drust, B., and Erskine, R. M. (2016). Genetic variation and exercise-induced muscle damage: implications for athletic performance, injury and ageing. Eur. J. Appl. Physiol. 116, 1595–1625. doi: 10.1007/s00421-016-3411-1
Chen, J., Chen, J. S., Li, S., Zhang, F., Deng, J., Zeng, L. H., et al. (2024). Amyloid precursor protein: a regulatory hub in Alzheimer’s Disease. Aging Dis. 15, 201–225. doi: 10.14336/AD.2023.0308
Citron, M. (2002). Emerging Alzheimer’s disease therapies: inhibition of beta-secretase. Neurobiol. Aging 23, 1017–1022. doi: 10.1016/s0197-4580(02)00122-7
Cui, K., Li, C., and Fang, G. (2023). Aerobic exercise delays Alzheimer’s Disease by regulating mitochondrial proteostasis in the cerebral cortex and hippocampus. Life 13:1204. doi: 10.3390/life13051204
Dehvari, N., Isacsson, O., Winblad, B., Cedazo-Minguez, A., and Cowburn, R. F. (2008). Presenilin regulates extracellular regulated kinase (Erk) activity by a protein kinase C alpha dependent mechanism. Neurosci. Lett. 436, 77–80. doi: 10.1016/j.neulet.2008.02.063
Downey, C. L., Young, A., Burton, E. F., Graham, S. M., Macfarlane, R. J., Tsapakis, E. M., et al. (2017). Dementia and osteoporosis in a geriatric population: is there a common link? World J Orthop. 8, 412–423. doi: 10.5312/wjo.v8.i5.412
Duan, R., Hong, C. G., Chen, M. L., Wang, X., Pang, Z. L., Xie, H., et al. (2023). Targeting autophagy receptors OPTN and SQSTM1 as a novel therapeutic strategy for osteoporosis complicated with Alzheimer’s disease. Chem. Biol. Interact. 377:110462. doi: 10.1016/j.cbi.2023.110462
El Kadmiri, N., Slassi, I., El Moutawakil, B., Nadifi, S., Tadevosyan, A., Hachem, A., et al. (2014). Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and Alzheimer’s disease. Pathol. Biol. 62, 333–336. doi: 10.1016/j.patbio.2014.08.002
Funamoto, S., Tagami, S., Okochi, M., and Morishima-Kawashima, M. (2020). Successive cleavage of β-amyloid precursor protein by γ-secretase. Semin. Cell. Dev. Biol. 105, 64–74. doi: 10.1016/j.semcdb.2020.04.002
Gaitán, J. M., Moon, H. Y., Stremlau, M., Dubal, D. B., Cook, D. B., Okonkwo, O. C., et al. (2021). Effects of aerobic exercise training on systemic biomarkers and cognition in late middle-aged adults at risk for Alzheimer’s Disease. Front. Endocrinol. 12:660181. doi: 10.3389/fendo.2021.660181
Gehlot, P., Kumar, S., Kumar Vyas, V., Singh Choudhary, B., Sharma, M., and Malik, R. (2022). Guanidine-based β amyloid precursor protein cleavage enzyme 1 (BACE-1) inhibitors for the Alzheimer’s disease (AD): a review. Bioorg. Med. Chem. 74:117047. doi: 10.1016/j.bmc.2022.117047
Gökçe, E., and Gün, N. (2023). The relationship between exercise, cathepsin B, and cognitive functions: systematic review. Percept. Mot. Skills 130, 1366–1385. doi: 10.1177/00315125231176980
Grimes, M. T., Powell, M., Gutierrez, S. M., Darby-King, A., Harley, C. W., and McLean, J. H. (2015). Epac activation initiates associative odor preference memories in the rat pup. Learn. Mem. 22, 74–82. doi: 10.1101/lm.037101.114
Guan, P. P., and Wang, P. (2019). Integrated communications between cyclooxygenase-2 and Alzheimer’s disease. FASEB J. 33, 13–33. doi: 10.1096/fj.201800355RRRR
Guéniot, L., Lepere, V., De Medeiros, G. F., Danckaert, A., Flamant, P., Le Dudal, M., et al. (2020). Muscle injury induces postoperative cognitive dysfunction. Sci. Rep. 10:2768. doi: 10.1038/s41598-020-59639-3
Guerrero-Hue, M., Vallejo-Mudarra, M., García-Caballero, C., Córdoba-David, G. M., Palomino-Antolín, A., Herencia, C., et al. (2023). Tweak/Fn14 system is involved in rhabdomyolysis-induced acute kidney injury. Biomed. Pharmacother. 169:115925. doi: 10.1016/j.biopha.2023.115925
Guo, C., Yang, Z. H., Zhang, S., Chai, R., Xue, H., Zhang, Y. H., et al. (2017). Intranasal Lactoferrin Enhances α-Secretase-dependent amyloid precursor protein processing via the ERK1/2-CREB and HIF-1α pathways in an Alzheimer’s Disease mouse model. Neuropsychopharmacology 42, 2504–2515. doi: 10.1038/npp.2017.8
Guo, Y., Sun, T., Wang, X., Li, S., and Liu, Z. (2014). Cognitive impairment and 1-year outcome in elderly patients with hip fracture. Med. Sci. Monit. 20, 1963–1968. doi: 10.12659/MSM.892304
Hardy, J. A., and Higgins, G. A. (1992). Alzheimer’s disease: the amyloid cascade hypothesis. Science 256, 184–185. doi: 10.1126/science.1566067
Heneka, M. T., Carson, M. J., El Khoury, J., Landreth, G. E., Brosseron, F., Feinstein, D. L., et al. (2015). Neuroinflammation in Alzheimer’s disease. Lancet Neurol. 14, 388–405. doi: 10.1016/S1474-4422(15)70016-5
Herath, M., Cohen, A., Ebeling, P. R., and Milat, F. (2022). Dilemmas in the management of osteoporosis in younger adults. JBMR Plus 6:e10594. doi: 10.1002/jbm4.10594
Hoffmann, K., Sobol, N. A., Frederiksen, K. S., Beyer, N., Vogel, A., Vestergaard, K., et al. (2016). Moderate-to-high intensity physical exercise in patients with Alzheimer’s disease: a randomized controlled trial. J. Alzheimers Dis. 50, 443–453. doi: 10.3233/JAD-150817
Huang, B., Chen, K., and Li, Y. (2023). Aerobic exercise, an effective prevention and treatment for mild cognitive impairment. Front. Aging Neurosci. 15:1194559. doi: 10.3389/fnagi.2023.1194559
Ishimoto, A. K., and Shah, A. A. (2024). Screening and early treatment for osteoporosis: Who are we missing under age 65? Maturitas 187:108044. doi: 10.1016/j.maturitas.2024.108044
Jang, S., Chapa-Dubocq, X. R., Parodi-Rullán, R. M., Fossati, S., and Javadov, S. (2022). Beta-Amyloid instigates dysfunction of mitochondria in cardiac cells. Cells 11:373. doi: 10.3390/cells11030373
Johnston, C. B., and Dagar, M. (2020). Osteoporosis in older adults. Med. Clin. North Am. 104, 873–884. doi: 10.1016/j.mcna.2020.06.004
Kang, E. B., Kwon, I. S., Koo, J. H., Kim, E. J., Kim, C. H., Lee, J., et al. (2013). Treadmill exercise represses neuronal cell death and inflammation during Aβ-induced ER stress by regulating unfolded protein response in aged presenilin 2 mutant mice. Apoptosis 18, 1332–1347. doi: 10.1007/s10495-013-0884-9
Kang, S. H., Lee, K. H., Chang, Y., Choe, Y. S., Kim, J. P., Jang, H., et al. (2022). Gender-specific relationship between thigh muscle and fat mass and brain amyloid-β positivity. Alzheimers Res. Ther. 14:145. doi: 10.1186/s13195-022-01086-5
Koriyama, Y., Hori, A., Ito, H., Yonezawa, S., Baba, Y., Tanimoto, N., et al. (2021). Discovery of Atabecestat (JNJ-54861911): a thiazine-based β-Amyloid precursor protein cleaving enzyme 1 inhibitor advanced to the phase 2b/3 EARLY clinical trial. J. Med. Chem. 64, 1873–1888. doi: 10.1021/acs.jmedchem.0c01917
Lee, Y. Y., Yang, Y. P., Huang, P. I., Li, W. C., Huang, M. C., Kao, C. L., et al. (2015). Exercise suppresses COX-2 pro-inflammatory pathway in vestibular migraine. Brain Res. Bull. 116, 98–105. doi: 10.1016/j.brainresbull.2015.06.005
Liang, S., Liu, H., Wang, X., Lin, H., Zheng, L., Zhang, Y., et al. (2025). Aerobic exercise improves clearance of amyloid-β via the glymphatic system in a mouse model of Alzheimer’s Disease. Brain Res. Bull. 222:111263. doi: 10.1016/j.brainresbull.2025.111263
Lichtenthaler, S. F., and Haass, C. (2004). Amyloid at the cutting edge: activation of alpha-secretase prevents amyloidogenesis in an Alzheimer disease mouse model. J. Clin. Invest. 113, 1384–1387. doi: 10.1172/JCI21746
Liu, Y., Chu, J. M. T., Yan, T., Zhang, Y., Chen, Y., Chang, R. C. C., et al. (2020). Short-term resistance exercise inhibits neuroinflammation and attenuates neuropathological changes in 3xTg Alzheimer’s disease mice. J. Neuroinflammation 17:4. doi: 10.1186/s12974-019-1653-7
Liu, Y., Sugiura, Y., Chen, F., Lee, K. F., Ye, Q., and Lin, W. (2019). Blocking skeletal muscle DHPRs/Ryr1 prevents neuromuscular synapse loss in mutant mice deficient in type III Neuregulin 1 (CRD-Nrg1). PLoS Genet. 15:e1007857. doi: 10.1371/journal.pgen.1007857
Lopez, J. R., and Shtifman, A. (2010). Intracellular β-amyloid accumulation leads to age-dependent progression of Ca2+ dysregulation in skeletal muscle. Muscle Nerve 42, 731–738. doi: 10.1002/mus.21745
Luo, D., Wong, W. C., Li, Z., Qin, G., Lan, Z., Mo, F., et al. (2025). The relationship between pain catastrophizing and cognitive frailty in patients with lumbar disc herniation mediated by sleep quality: the regulatory effect of emotions- a retrospective study. Eur. Spine J. [Online ahead of print]. doi: 10.1007/s00586-025-09449-w
Luo, G., Xu, H., Huang, Y., Mo, D., Song, L., Jia, B., et al. (2016). Deposition of BACE-1 protein in the brains of APP/PS1 double transgenic mice. Biomed. Res. Int. 2016:8380618. doi: 10.1155/2016/8380618
Mackay, E. A., Ehrhard, A., Moniatte, M., Guenet, C., Tardif, C., Tarnus, C., et al. (1997). A possible role for cathepsins D, E, and B in the processing of beta-amyloid precursor protein in Alzheimer’s disease. Eur. J. Biochem. 244, 414–425. doi: 10.1111/j.1432-1033.1997.00414.x
Marston, K. J., de Frutos-Lucas, J., Porter, T., Milicic, L., Vacher, M., Sewell, K. R., et al. (2024). Exploration of Alzheimer’s disease-related gene expression following high-intensity and moderate-intensity exercise interventions. J. Sci. Med. Sport 27, 828–833. doi: 10.1016/j.jsams.2024.07.017
Morris, J. K., Vidoni, E. D., Johnson, D. K., Van Sciver, A., Mahnken, J. D., Honea, R. A., et al. (2017). Aerobic exercise for Alzheimer’s disease: a randomized controlled pilot trial. PLoS One 12:e0170547. doi: 10.1371/journal.pone.0170547
Moussa, N., and Dayoub, N. (2023). Exploring the role of COX-2 in Alzheimer’s disease: potential therapeutic implications of COX-2 inhibitors. Saudi Pharm. J. 31:101729. doi: 10.1016/j.jsps.2023.101729
Müller, U. C., Deller, T., and Korte, M. (2017). Not just amyloid: physiological functions of the amyloid precursor protein family. Nat. Rev. Neurosci. 18, 281–298. doi: 10.1038/nrn.2017.29
Nasme, F., Behera, J., Tyagi, P., Debnath, N., Falcone, J. C., and Tyagi, N. (2025). The potential link between the development of Alzheimer’s disease and osteoporosis. Biogerontology 26:43. doi: 10.1007/s10522-024-10181-z
Nathan, N. (2023). Rhabdomyolysis and hepatic injury. Anesth. Analg 136:841. doi: 10.1213/ANE.0000000000006482
Nicholls, C., Li, H., and Liu, J. P. (2012). GAPDH: a common enzyme with uncommon functions. Clin. Exp. Pharmacol. Physiol. 39, 674–679. doi: 10.1111/j.1440-1681.2011.05599.x
Oh, E. S., Blennow, K., Bigelow, G. E., Inouye, S. K., Marcantonio, E. R., Neufeld, K. J., et al. (2018). Abnormal CSF amyloid-β42 and tau levels in hip fracture patients without dementia. PLoS One 13:e0204695. doi: 10.1371/journal.pone.0204695
Pahlavani, H. A. (2023). Exercise therapy to prevent and treat Alzheimer’s disease. Front. Aging Neurosci. 15:1243869. doi: 10.3389/fnagi.2023.1243869
Peng, S., Zhang, Y., Zhang, J., Wang, H., and Ren, B. E. R. K. (2010). in learning and memory: a review of recent research. Int. J. Mol. Sci. 11, 222–232. doi: 10.3390/ijms11010222
Pimentel Neto, J., Rocha-Braga, L. C., Fior, M. B., Camargo, P. O., and Ciena, A. P. (2025). Structural proteins at neuromuscular junction are downgraded while NRG1 and agrin gene expression increases after muscle injury. Biomedicines 13:2277. doi: 10.3390/biomedicines13092277
Qin, W., Ho, L., Pompl, P. N., Peng, Y., Zhao, Z., Xiang, Z., et al. (2003). Cyclooxygenase (COX)-2 and COX-1 potentiate beta-amyloid peptide generation through mechanisms that involve gamma-secretase activity. J. Biol. Chem. 278, 50970–50977. doi: 10.1074/jbc.M307699200
Quadros, A., Patel, N., Crescentini, R., Crawford, F., Paris, D., and Mullan, M. (2003). Increased TNFalpha production and Cox-2 activity in organotypic brain slice cultures from APPsw transgenic mice. Neurosci. Lett. 353, 66–68. doi: 10.1016/j.neulet.2003.08.076
Rosen, K. M., Ford, B. D., and Querfurth, H. W. (2003). Downregulation and increased turnover of beta-amyloid precursor protein in skeletal muscle cultures by neuregulin-1. Exp. Neurol. 181, 170–180. doi: 10.1016/s0014-4886(03)00031-1
Rossi Daré, L., Garcia, A., Neves, B. H., and Mello-Carpes, P. B. (2020). One physical exercise session promotes recognition learning in rats with cognitive deficits related to amyloid beta neurotoxicity. Brain Res. 1744:146918. doi: 10.1016/j.brainres.2020.146918
Selkoe, D. J. (2008). Soluble oligomers of the amyloid beta-protein impair synaptic plasticity and behavior. Behav. Brain Res. 192, 106–113. doi: 10.1016/j.bbr.2008.02.016
Seo, T. B., Cho, Y. H., Sakong, H., and Kim, Y. P. (2021). Effect of treadmill exercise and bone marrow stromal cell engraftment on activation of BDNF-ERK-CREB signaling pathway in the crushed sciatic nerve. J. Exerc. Rehabil. 17, 403–409. doi: 10.12965/jer.2142626.313
Sepúlveda-Lara, A., Sepúlveda, P., and Marzuca-Nassr, G. N. (2024). Resistance exercise training as a new trend in Alzheimer’s Disease research: from molecular mechanisms to prevention. Int. J. Mol. Sci. 25:7084. doi: 10.3390/ijms25137084
Shi, C., Zheng, D. D., Fang, L., Wu, F., Kwong, W. H., and Xu, J. (2012). Ginsenoside Rg1 promotes nonamyloidgenic cleavage of APP via estrogen receptor signaling to MAPK/ERK and PI3K/Akt. Biochim. Biophys. Acta 1820, 453–460. doi: 10.1016/j.bbagen.2011.12.005
Singh, N., Benoit, M. R., Zhou, J., Das, B., Davila-Velderrain, J., Kellis, M., et al. (2022a). BACE-1 inhibition facilitates the transition from homeostatic microglia to DAM-1. Sci. Adv. 8:eabo1286. doi: 10.1126/sciadv.abo1286
Singh, N., Das, B., Zhou, J., Hu, X., and Yan, R. (2022b). Targeted BACE-1 inhibition in microglia enhances amyloid clearance and improved cognitive performance. Sci. Adv. 8:eabo3610. doi: 10.1126/sciadv.abo3610
Smith, C. R., Harty, P. S., Stecker, R. A., and Kerksick, C. M. A. (2019). Pilot study to examine the impact of beta-alanine supplementation on anaerobic exercise performance in collegiate rugby athletes. Sports 7:231. doi: 10.3390/sports7110231
Stapledon, C. J. M., Stamenkov, R., Cappai, R., Clark, J. M., Bourke, A., Bogdan Solomon, L., et al. (2021). Relationships between the bone expression of Alzheimer’s disease-related genes, bone remodelling genes and cortical bone structure in neck of femur fracture. Calcif. Tissue Int. 108, 610–621. doi: 10.1007/s00223-020-00796-y
Stein, T. D., Montenigro, P. H., Alvarez, V. E., Xia, W., Crary, J. F., Tripodis, Y., et al. (2015). Beta-amyloid deposition in chronic traumatic encephalopathy. Acta Neuropathol. 130, 21–34. doi: 10.1007/s00401-015-1435-y
Sui, H. J., Zhang, L. L., Liu, Z., and Jin, Y. (2015). Atorvastatin prevents Aβ oligomer-induced neurotoxicity in cultured rat hippocampal neurons by inhibiting Tau cleavage. Acta Pharmacol. Sin. 36, 553–564. doi: 10.1038/aps.2014.161
Tischer, E., and Cordell, B. (1996). Beta-amyloid precursor protein. Location of transmembrane domain and specificity of gamma-secretase cleavage. J. Biol. Chem. 271, 21914–21919. doi: 10.1074/jbc.271.36.21914
Tomita, T. (2008). At the frontline of Alzheimer’s disease treatment: gamma-secretase inhibitor/modulator mechanism. Naunyn Schmiedebergs Arch. Pharmacol. 377, 295–300. doi: 10.1007/s00210-007-0206-2
Tunesi, M., Izzo, L., Raimondi, I., Albani, D., and Giordano, C. (2020). A miniaturized hydrogel-based in vitro model for dynamic culturing of human cells overexpressing beta-amyloid precursor protein. J. Tissue Eng. 11:2041731420945633. doi: 10.1177/2041731420945633
Vassar, R., Bennett, B. D., Babu-Khan, S., Kahn, S., Mendiaz, E. A., Denis, P., et al. (1999). Beta-secretase cleavage of Alzheimer’s amyloid precursor protein by the transmembrane aspartic protease BACE. Science 286, 735–741. doi: 10.1126/science.286.5440.735
Venezia, V., Nizzari, M., Repetto, E., Violani, E., Corsaro, A., Thellung, S., et al. (2006). Amyloid precursor protein modulates ERK-1 and -2 signaling. Ann. N. Y. Acad. Sci. 1090, 455–465. doi: 10.1196/annals.1378.048
Venugopal, C., Demos, C. M., Rao, K. S., Pappolla, M. A., and Sambamurti, K. (2008). Beta-secretase: structure, function, and evolution. CNS Neurol Disord. Drug Targets 7, 278–294. doi: 10.2174/187152708784936626
Walker, M. D., and Shane, E. (2023). Postmenopausal osteoporosis. N. Engl. J. Med. 389, 1979–1991. doi: 10.1056/NEJMcp2307353
Wang, H., Ma, G., Min, J., Li, J., Shan, W., and Zuo, Z. (2023). Inhibition of ERK/CREB signaling contributes to postoperative learning and memory dysfunction in neonatal rats. J. Mol. Med. 101, 265–278. doi: 10.1007/s00109-023-02285-9
Wang, H. S., Karnik, S. J., Margetts, T. J., Plotkin, L. I., Movila, A., Fehrenbacher, J. C., et al. (2024). Mind gaps and bone snaps: exploring the connection between alzheimer’s disease and osteoporosis. Curr. Osteoporos Rep. 22, 483–494. doi: 10.1007/s11914-023-00851-1
Wang, J., Yu, X., Cao, X., Tan, L., Jia, B., Chen, R., et al. (2023). GAPDH: a common housekeeping gene with an oncogenic role in pan-cancer. Comput. Struct. Biotechnol. J. 21, 4056–4069. doi: 10.1016/j.csbj.2023.07.034
Wang, R., Zhang, Y. W., Sun, P., Liu, R., Zhang, X., Zhang, X., et al. (2006). Transcriptional regulation of PEN-2, a key component of the gamma-secretase complex, by CREB. Mol. Cell Biol. 26, 1347–1354. doi: 10.1128/MCB.26.4.1347-1354.2006
Wang, X., Fu, S. Q., Yuan, X., Yu, F., Ji, Q., Tang, H. W., et al. (2024). A GAPDH serotonylation system couples CD8+ T cell glycolytic metabolism to antitumor immunity. Mol. Cell 84, 760–775.e7. doi: 10.1016/j.molcel.2023.12.015.
Yang, H., Xuefeng, Y., Shandong, W., and Jianhua, X. (2020). COX-2 in liver fibrosis. Clin. Chim. Acta 506, 196–203. doi: 10.1016/j.cca.2020.03.024
Yonemura, Y., Futai, E., Yagishita, S., Suo, S., Tomita, T., Iwatsubo, T., et al. (2011). Comparison of presenilin 1 and presenilin 2 γ-secretase activities using a yeast reconstitution system. J. Biol. Chem. 286, 44569–44575. doi: 10.1074/jbc.M111.270108
Yook, J. S., and Cho, J. Y. (2017). Treadmill exercise ameliorates the regulation of energy metabolism in skeletal muscle of NSE/PS2mtransgenic mice with Alzheimer’s disease. J. Exerc. Nutr. Biochem. 21, 40–47. doi: 10.20463/jenb.2017.0046
Yu, F., Vock, D. M., Zhang, L., Salisbury, D., Nelson, N. W., Chow, L. S., et al. (2021). Cognitive effects of aerobic exercise in Alzheimer’s Disease: a pilot randomized controlled trial. J. Alzheimers Dis. 80, 233–244. doi: 10.3233/JAD-201100
Yu, F., Xu, B., Song, C., Ji, L., and Zhang, X. (2013). Treadmill exercise slows cognitive deficits in aging rats by antioxidation and inhibition of amyloid production. Neuroreport 24, 342–347. doi: 10.1097/WNR.0b013e3283606c5e
Zhao, L., Yan, W., Xiang, H., Wang, X., and Qiao, H. (2012). Proteomic investigation of changes in rat skeletal muscle after exercise-induced fatigue. Biol. Res. 45, 75–80. doi: 10.4067/S0716-97602012000100010
Zhao, Y., Chen, H., Qiu, F., He, J., and Chen, J. (2023). Cognitive impairment and risks of osteoporosis: a systematic review and meta-analysis. Arch. Gerontol. Geriatr. 106:104879. doi: 10.1016/j.archger.2022.104879
Zhen, W., Zhen, H., Wang, Y., Chen, L., Niu, X., Zhang, B., et al. (2023). Mechanism of ERK/CREB pathway in pain and analgesia. Front. Mol. Neurosci. 16:1156674. doi: 10.3389/fnmol.2023.1156674
Zheng, Q., and Wang, X. (2025). Alzheimer’s disease: insights into pathology, molecular mechanisms, and therapy. Protein Cell 16, 83–120. doi: 10.1093/procel/pwae026
Zhou, S., Chen, S., Liu, X., Zhang, Y., Zhao, M., and Li, W. (2022). Physical activity improves cognition and activities of daily living in adults with Alzheimer’s disease: a systematic review and meta-analysis of randomized controlled trials. Int. J. Environ. Res. Public Health 19:1216. doi: 10.3390/ijerph19031216
Keywords: exercise, exercise-related injury, processing, synthesis, β-amyloid, β-amyloid precursor protein
Citation: Zhen W, Xing Y, Li Y, Hao J, Kong L and Zhen H (2026) β-amyloid and β-amyloid precursor protein synthesis and processing: effects of exercise and exercise-related injury. Front. Cell. Neurosci. 20:1735542. doi: 10.3389/fncel.2026.1735542
Received: 30 October 2025; Revised: 25 December 2025; Accepted: 19 January 2026;
Published: 09 February 2026.
Edited by:
Rebecca E. K. MacPherson, Brock University, CanadaReviewed by:
Jon Storm-Mathisen, University of Oslo, NorwayVijay Sankar Ramasamy, Chosun University, Republic of Korea
Copyright © 2026 Zhen, Xing, Li, Hao, Kong and Zhen. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Weizhe Zhen, end6MjAxN2J1Y21AMTYzLmNvbQ==; Hongjun Zhen, emhqMDY4QDE2My5jb20=