Exercise-induced neurogenesis through BDNF-TrkB pathway: implications for neurodegenerative disorders

Jun Jie Lee; Patrick Henry Sebastian Sitjar; Eng Tat Ang; Jorming Goh

doi:10.1515/teb-2024-0038

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Exercise-induced neurogenesis through BDNF-TrkB pathway: implications for neurodegenerative disorders

Jun Jie Lee , Patrick Henry Sebastian Sitjar , Eng Tat Ang und Jorming Goh

Veröffentlicht/Copyright: 25. Februar 2025

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Aus der Zeitschrift Translational Exercise Biomedicine Band 2 Heft 1

Abstract

Current scientific endeavours in the field of geroscience have begun to reveal how factors such as exercise could modulate the brain aging process. In this review, we ask how exercise could potentially modulate aging, and by extension, the development of Alzheimer’s Disease (AD). Furthermore, we discuss how exercise could mitigate the cascade of debilitating manifestations in AD. Mechanistically, we discuss how biomolecules such as brain-derived neurotrophic factor (BDNF) and its cognate receptor, tropomyosin receptor kinase B (TrkB) could change during the life course and how its signalling pathways could be altered with exercise (acute sessions or chronic training). Tackling these questions could help the scientific and medical community mitigate age-related decline in terms of neurological functions.

Keywords: exercise; BDNF; neurogenesis; Alzheimer’s disease

Introduction

In the past decade, the field of geroscience has accelerated the understanding of the aging process. Aging encompasses the deterioration of primary biological processes, driven by intrinsic factors such as telomere shortening, oxidative stress, and mitochondrial dysfunction, which are central to biological theories like the free radical theory and antagonistic pleiotropy [1], 2]. Secondary processes on the other hand, are influenced by external factors like environmental exposures, lifestyle habits, and non-communicable diseases such as type 2 diabetes or cardiovascular diseases [3]. Secondary aging can also arise from metabolic consequences of primary mechanisms, such as mitochondrial decline leading to metabolic dysregulation; this highlights the cyclic and interdependent relationships between primary and secondary aging, with intrinsic changes amplifying external vulnerabilities and vice versa [1], 4]. The human body relies on the coordinated functions of various organ systems to sustain life. However, the effects of aging manifest differently across organs, with some being more susceptible to accelerated decline. For instance, the brain is particularly vulnerable to aging, where accelerated aging is closely associated with the development of neurodegenerative diseases [5], 6]. This process is driven by intrinsic factors, environmental exposures, and underlying disease pathologies [7], [8], [9]; one such example being Alzheimer’s Disease (AD), which is characterized by hallmark features such as the formation of neurofibrillary tangles, extracellular amyloid plaques, and progressive hippocampal atrophy [10], 11]. In 2023, around 6.7 million people aged 65 years and older in the United States of America were estimated to have AD [12] and by 2050, the worldwide prevalence is expected to be 1 in 85 individuals [13]. These figures are fuelled in large part by the aging baby boomer generation. It is imperative that more needs to be done to slow the prevalence of AD, otherwise the escalating level of medical and social care needed for managing AD could turn into a worldwide crisis. Exercise training is a cost-effective solution in preventing age-related neurodegeneration. Like the aging process, exercise training exerts pleiotropic effects on multiple organ systems. This review will discuss how exercise training, involving the periphery organs, such as skeletal muscle, can affect brain aging and health. The summary of this article is presented in Figure 1.

Figure 1:

Graphical representation of this study. Key points: (1) this review bridges the gap in understanding how exercise-induced modulation of the BDNF-TrkB signaling pathway influences neurogenesis and mitigates neurodegeneration, focusing on mechanisms like neurotrophin upregulation. (2) Relevant information was synthesized from preclinical and clinical studies to evaluate exercise’s role in enhancing BDNF-TrkB signaling, addressing its impact on neurodegeneration, particularly in Alzheimer’s disease. (3) Findings suggest exercise enhances neurogenesis, cognitive function, and neuroprotection through BDNF-TrkB signaling, offering low-cost strategies to mitigate age-related neurological decline and support clinical interventions for neurodegenerative disorders. Figure created with BioRender.

Effects of exercise on the brain

As early as the 19th century, the concept of the nervous system being plastic was proposed by a German physician named Johann Spurzheim (1815), and then again by Charles Darwin (1874). Both men suggested that increased usage of the brain would increase the size of the brain. At the turn of the 20th century, this idea was further substantiated when Ramón y Cajal proposed that increased usage of the brain would also improve the connectivity of the nervous system (see translation by DeFelipe and Jones, 1991) [14]. In 1938, Wolfgang Kohler theorized that the increased chemical composition of the nervous system could be associated with increased stimulation of the nervous system. In view of the above evidence, it is now generally accepted that brain plasticity can be modulated in response to both intrinsic and extrinsic influences. A complex living environment could induce changes in the brain weight and metabolism [15], 16]. Specifically, environmental enrichment involves stimuli which enhances physical, social, and cognitive environments, up-regulates neurotrophins (NTs) and their receptors [17] and possibly influences learning and memory [18]. In addition to environmental enrichment, the role of exercise training to improve neurogenesis was proposed [19]. More importantly, it was shown that physical exercise was more beneficial than an enriched environment in influencing neurogenesis in a pre-clinical animal model [20].

However, the molecular mechanisms through which regular exercise affects the structure and function of the brain remain incompletely understood. Physical exercise was reported to have profound effects on the brain’s neurochemistry and plasticity, with evidence demonstrating that it up-regulates neurotrophic factors (NT) such as nerve growth factor (NGF) and BDNF endogenously [21], [22], [23]. A positive correlation was identified between mRNA expression of NTs and the average distance ran per night when Sprague-Dawley male rats were given access to a running wheel [21], 22]. Of note, exercise-induced BDNF and NGF mRNA and protein upregulation in the hippocampal and caudal cortex regions of the brain – major areas involved in cognitive function, thus suggesting that exercise training could modulate age-associated neurodegeneration through supportive effect on neuronal development and survival [21], 22].

Such NTs were also involved in facilitating recovery from brain injury such as stroke [24]. The role of acute pre-conditioning exercise in reducing mortality and brain damage was also observed in male Mongolian gerbils, whereby access to running wheels for 14 days prior to anesthetized carotid occlusion (15 or 20 min) resulted in greater survival (90 or 100 %, from 15 or 20 min carotid occlusion respectively), compared with gerbils without access to running wheel (44 or 21 %, from 15 or 20 min carotid occlusion respectively) [25]. Further, quantitative histological analysis revealed that the running group was conferred with neuroprotection as identified by a reduced infarct area in the thalamus and limited neuronal damage in the cortex, striatum and hippocampus [25].

In a pre-clinical rat model of Parkinson’s Disease, it was proposed that forced exercise training could protect the brain from oxidative stress that is found to be toxic to dopaminergic (DA) neurons [26]. Striatal glial cell line-derived neurotrophic factor (GDNF) of the transforming growth factor β (TGF-β) superfamily was found to be a molecule of interest [26]. Such factors were upregulated and triggered downstream signaling cascades enzymes such as extra-cellular signal regulated kinases (ERK), which were elevated [26]. The exact mechanism is yet to be elucidated but it is likely that exercise-induced neuroprotection occurs through trophic support of DA neurons. Interestingly, it was shown that voluntary wheel running exercise could regulate basic fibroblast growth factor (bFGF) expression, thus implicating growth factors to as potential mediators of the positive effects of exercise on the brain [27].

A recent systematic review by Renke et al. highlighted that both acute mild-to-moderate intensity aerobic exercise, and chronic exercise training increase cerebral blood flow (CBF), which typically declines with age and in neuropsychiatric conditions [28], [29], [30], [31]. While the long-term effects of chronic exercise training on basal CBF and cognitive function remain uncertain [28], increased CBF may facilitate the delivery of NTs to neurons, potentially preventing degeneration. Interestingly, not only do exercise intensity and schedule influence CBF, but breathing conditions during exercise may also play a crucial role. For example, nasal breathing during a graded maximal exercise test significantly elevated CBF compared to oral or combined breathing in young healthy males [32]. This finding suggests that incorporating nasal breathing strategies into exercise interventions could enhance CBF modulation and potentially improve NT delivery, opening new avenues for maximizing cognitive benefits through targeted exercise regimens.

Another study by Draganski et al. highlighted that neuromuscular movement training conferred neuroprotection; their findings challenged the traditionally held belief that although skill training could alter cortical plasticity, this change was associated only with functional, rather than anatomical changes [33]. The investigators reported grey matter changes were detected using brain imaging. Taking this finding into consideration, exercise training might also lead to similar effects. A review by Erickson et al. identified that there was indeed a positive association between cardiorespiratory fitness levels and gray matter volume in the prefrontal cortex, temporal lobes and hippocampus of older adults as detected using magnetic resonance imaging (MRI) [34]. In addition, fitness levels were also associated with improved cognitive performance, suggesting that optimizing the volume and intensity of exercise training should be considered for enhancing both cardiopulmonary fitness and brain health.

There are also known psychological benefits associated with running, such as positive mood changes and decreased levels of anxiety [35], 36]. Oswald et al. identified that any form of running or jogging intervention benefited mental health outcomes compared with sedentary groups (including psychiatric and homeless participants) [37], 38]. Interestingly, even single acute bouts of running showed significant mental health improvement. In 22 out of 23 studies, utilizing single acute bouts of running (from treadmill or track, indoor or outdoor, timed or leisure pace) significantly enhanced mental health improvement post-run, including reductions in anxiety, depression, confusion and mood disturbance [37].

Despite these findings, attempts to uncover the mechanistic actions of exercise on transcriptomic and phenotypic changes have been inconsistent, often hindered by differences in protocols and outcome measures. For instance, high-intensity interval training (HIIT), involving bouts at 70–85 % of peak aerobic capacity (VO₂max), contrasting the performance of moderate-intensity continuous (MIC) exercise (40–60 % VO₂max), has shown significant improvements in muscle strength, peak aerobic capacity, and serum BDNF among community-dwelling older adults [39], [40], [41], [42]. In contrast, studies involving older adults that were healthy or with mild to moderate AD alike have reported no differences between HIIT and MIC exercise in altering serum BDNF or neurocognitive performance [43], 44]. It indicates that the variance in response, despite similar exercise protocols, could possibly be attributed to individual differences in fitness levels, as the minimal effective intensity of exercise appears to depend on baseline fitness. Individuals with moderate-to-high levels of cardiopulmonary fitness often require a higher threshold of exercise intensity (e.g., ≥45 % of VO₂ reserve) to achieve measurable benefits, whereas individuals with lower fitness may respond to intensities as low as 30 % of VO₂ reserve [45]. This warrants further studies delving into measuring baseline fitness levels, and its incorporation into exercise prescription.

BDNF signalling in health and disease

BDNF is widely known as a neurotrophin, a member of the nerve growth factor that promotes neuronal survival [46]. Besides implications for childhood and adolescence, BDNF plays a significant role in the adult brain. Synaptic plasticity for one, is mediated by BDNF’s action on its cognate receptor, TrkB, wherein activation of downstream signalling for survival, phosphorylation and hence giving rise to eventual memory modulation [47], 48]. This is consistent with the fact that increased activity-dependent BDNF secretion is associated with the size of the hippocampus [10], 49].

BDNF-TrkB signalling is paramount in the development of new neurons as well as their incorporation into hippocampal circuits. The implication of BDNF-TrkB signalling on basal neurogenesis is observed in animal models, where BDNF and TrkB knockdown mice had significantly reduced neuronal stem cell proliferation, compared with wildtype mice [50]. In addition, neuronal stem cells isolated from knockdown mice died prior to differentiation and maturation [51]. On the other hand, elevated BDNF expression enhanced in vivo proliferation, initiation of differentiation, axonal path migration and maturation of neural stem cells [50]. Further, exogenous treatment using adenovirus vector carrying the BDNF gene improved neuron recruitment in adult rat brains [52]. Ultimately, it has been extensively reported that BDNF signalling is lower in patients with neuropsychiatric diseases and neurodegeneration [53], [54], [55]. As such, BDNF signalling is likely necessary for plasticity, neurogenesis and when deficient, leads to neurodegeneration.

BDNF is modulated by age and exercise

BDNF expression decreases with age in the human hippocampus, possibly explaining an age-related decline in memory and learning [10], 56]. However, BDNF secretion does not appear to be modulated by aging, and can be upregulated by exercise regardless of age [57]. Circulating endogenous BDNF could arise from the brain, or platelets [49], 58], 59]. Skeletal Muscle has been shown to upregulate endogenous BDNF expression in response to exercise as well, but they are not released into the periphery [60]. On the other hand, BDNF levels has been found to decrease after exercise which indicates that it may cross the blood-brain barrier (BBB) into the central nervous system (CNS) to implement its effects on the brain [61]. As such, serum BDNF levels may indicate brain levels, but it is still unclear however, the definite contributions of each BDNF source to the total BDNF in circulation.

It was suggested that fibronectin type III domain-containing protein (FNDC) 5, an exercise-induced, secreted factor from skeletal muscle induces hippocampal BDNF gene expression [62]. Indeed, acute aerobic exercise has been shown to increase endogenous concentrations of BDNF as well, in populations ranging from healthy adults to the elderly, and even in diseased populations such as AD patients [10], 49], [63], [64], [65], [66], [67]. Interestingly, resting serum concentrations of BDNF has an inverse relationship with VO₂max and frequency of exercise, but remained responsive towards acute bouts of exercise [68]. This is suggestive of a training effect for BDNF secretion and does suggest that increased protein expression at baseline is not necessarily beneficial. Long-term exercise training showed lower concentrations of resting serum BDNF concentrations in young and middle-aged men, likely an upregulation of BDNF binding sites as a physiological adaptation to exercise training [69], 70].

It remains debatable whether BDNF can cross the blood brain barrier, but evidence thus far has been supportive. Pan et al., demonstrated a probable involvement of a saturable transporter, alongside Rasmussen et al., suggesting up to 80 % of peripheral BDNF are derived from centrally secreted BDNF [49], 71]. However, it must not be misunderstood that a unidirectional transport occurs across the blood brain barrier. Schmidt and Duman have shown the effect of serum BDNF both as a biomarker, and as a possible adjuvant for major depressive disorders when administered into the blood [72]. Furthermore, BDNF is capable of regulating the immune system [73], 74], and the modulation of chronic inflammation of the central nervous system [75], 76]. Both peripheral and cerebral BDNF/TrkB signalling has also been found to be implicated with cardiovascular and peripheral energy metabolism [77], 78]. Interestingly, exercise-induced BDNF signalling may also be involved in pro-survival Bcl-2 protein upregulation which could explain the benefits conferred with neurogenesis [78].

TrkB is modulated by age and exercise

TrkB is a receptor tyrosine kinase of the Trk family, otherwise known as neurotrophic tyrosine receptor kinase 2 (NTRK2). Beyond the discovery of BDNF peripherally in blood, the expression of TrkB can be found in many other tissues [79]. Expressed both in the central nervous system and in the periphery, such as on immune cells, TrkB serves as a conduit to intracellular signalling arising from BDNF activation [80]. Binding of BDNF to the full-length TrkB receptors results in the receptors dimerising and the autophosphorylation of intracellular tyrosine residues. This results in the activation of three specific signalling pathways downstream that mediate the effects of BDNF; the Ras–mitogen-activated protein kinase (MAPK) pathway, the phosphatidylinositol 3-kinase (PI3K)–Akt pathway and the PLCγ–Ca²⁺ pathway [81]. Activation of these pathways will lead to downstream effects that may be unique in different cell types. In neurons, cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) is a major mediator in the BDNF-TrkB signalling cascade and is activated either via the phospholipase C γ (PLCγ)/Ca²⁺/calmodulin kinase (CamK), or alternatively, through the Ras/ERK/Rsk pathway and regulates BDNF-induced gene expression [54], 82].

Therefore, individuals that engage in regular exercise are likely to have upregulated TrkB. Exercise (notwithstanding type/duration/intensity/frequency of exercise, participants profile) was found to increase TrkB mRNA expression in the brain [83], but not necessarily corresponding to protein levels [84]. TrkB expression was found to be regulated by a number of pathways; through protein kinase A (PKA)/CREB-dependent mechanisms [85], Ca²⁺-dependent regulation [85], and as well by BDNF [86]. Hence exercise could increase BDNF in immune cells via CREB-activation and leads to further upregulation of TrkB [87], 88], along with exercise induced increases in BDNF levels, it suggests the possibility for TrkB upregulation. The possibility of TrkB upregulation in fitter individuals (Figure 2) agrees with the findings by Currie et al., that lower circulating resting BDNF in individuals with higher VO₂max is a possible adaptation to avoid over-activation of the TrkB-BDNF pathway [89]. By the pharmacological receptor theory, increased receptor presence at the cell membrane heightens sensitivity of the cell towards the ligand stimulus [90], hence the reduced BDNF levels at rest is sufficient to maintain basal stimulation. Excessive activation is likely to be detrimental, given anecdotal data, which results in the down-regulation of TrkB receptor levels [84] with an increased likelihood of epilepsy [91]. Without the protective mechanism of lower circulating resting BDNF in individuals with higher VO₂max [89], chronically increased BDNF would result in enhanced activation of TrkB and lead to TrkB downregulation [92].

Webster et al., found significant reduction in both full length and truncated TrkB mRNA levels with aging [93]. While it could be argued that reduced mRNA levels do not necessarily correspond to reduced protein levels, pathological conditions such as diabetes, through advanced glycation end products (AGE) lead to the activation of endothelial upregulation of the matrix metalloproteinase, MMP9, results in the degradation of TrkB [94], 95]. The consequence of such degradation is the loss of BDNF-TrkB signalling, thus challenging survival of neurons. If the decrease in TrkB levels with aging is largely associated to AGE, exercise and appropriate diets could play a part to reduce AGE, hence raise TrkB levels [96].

How exercise modulation of BDNF-TrkB signalling could mitigate AD

BDNF and TrkB are strongly implicated in AD development, with studies associating lower levels of these proteins with increased risk of, or severity of symptoms, often linked to Aβ plaques or tangles [97]. While exercise has been suggested to modulate hippocampal atrophy and potentially mitigate aspects of AD pathology, the mechanisms underlying its effects remain only partially understood. One proposed mechanism involves exercise-induced increases in endogenous BDNF levels, which stimulate a rise in TrkB receptors [98], [99], [100], [101], [102]. This could enhance cellular sensitivity to BDNF signalling and potentially attenuate age-related hippocampal decline, thereby contributing to improved cognitive function [98], [99], [100], [101], [102]. However, more research is needed to confirm the extent and consistency of these effects in both preclinical and clinical contexts (Figure 2).

Figure 2:

Schematic of the relationships between training status, cardiopulmonary fitness and BDNF/ TrkB expression. (a) BDNF and TrkB expression and signaling decline with increased age, and is compromised in neurodegeneration, leading to diseases such as AD. (b) Exercise training has shown efficacy on the BDNF/ TrkB signaling pathways, as VO₂max is positively correlated with TrkB receptor expression, which sensitizes the cells to the BDNF ligand (at a lower basal concentration).

Experimental studies suggest that when BDNF/TrkB signalling is disrupted – for example, through ANA-12, a TrkB antagonist, exercise-related benefits are diminished. Similarly, in AD model rats, Aβ aggregation impairs hippocampal and cortical neurons, resulting in motor and cognitive dysfunction associated with reduced BDNF signalling. While exercise training has been shown to restore BDNF signalling and offer protective benefits in these models, ANA-12 treatment negated these effects [103]. Furthermore, Aβ deposits may exacerbate neuroinflammation and neuronal cell death, but exercise has been proposed to attenuate these processes via BDNF signalling, including the upregulation of pro-survival proteins [78], 103]. These findings, while promising, require additional validation in human studies to fully elucidate their implications for AD management.

Genetic factors also influence the variability in exercise outcomes. A BDNF polymorphism (Val66Met) associated with impaired cognitive reserve compared to normal genotypes offers one potential explanation for individual differences in exercise-induced neurological benefits [104], [105], [106], [107]. However, while this mutation may partially account for the variability, its role remains inconclusive, as other pathways likely contribute to exercise-induced neuroprotection [108], [109], [110]. Differences in exercise modality also appear to be important. For example, studies in mice indicate that forced exercise results in lower brain BDNF levels compared with voluntary exercise, possibly due to elevated cortisol levels [111]. Such observations support the promotion of voluntary physical activity in pre-clinical animal models, although further research is needed to determine its precise role in mitigating neurodegeneration in older adult humans.

Overall, while the existing literature suggests that exercise may have beneficial effects on AD pathology and neurodegeneration through mechanisms involving BDNF and TrkB signalling, the evidence remains preliminary. Future research is essential to validate these findings, understand individual variability, and explore alternative pathways contributing to exercise-related neurological improvements.

Conclusion

As the global population ages, physical exercise offers a promising, low-cost strategy to supplement neurodegenerative disease therapy. By enhancing BDNF-TrkB signalling, regular exercise not only improves cognitive function but could also slow age-related neurodegeneration. Future research should explore exercise interventions as therapeutic tools for conditions such as AD. The downstream effects of this signalling cascade activates the MAPK, PI3K and PLCγ pathways that confer multimodal benefits in cognition, neurogenesis and circuit integration. While acute exercise increases BDNF and TrkB levels in the short-term, chronic exercise training enhances signalling efficiency. Overall, this highlights that exercise is potentially beneficial for patients with AD or other forms of neurodegeneration. Moving forward, further research into a combination of exercise prescription and BDNF/TrkB signalling could offer an avenue to develop novel treatments or diagnostic capabilities concerning the elusive AD pathology whereby current diagnostic criteria are usually too late in detection [112], 113].

Corresponding author: Jorming Goh, Exercise Physiology & Biomarkers Laboratory, Yong Loo Lin School of Medicine, Healthy Longevity Translational Research Program, National University of Singapore (NUS), Singapore, Singapore; Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore, Singapore; Centre for Healthy Longevity, National University Health System (NUHS), Singapore, Singapore; Division of Medical Oncology, National Cancer Centre Singapore (NCCS), Singapore, Singapore; and Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore, E-mail: jorming@nus.edu.sg

Jun Jie Lee and Patrick Henry Sebastian Sitjar have contributed equally to this work.

Research ethics: Not applicable.
Informed consent: Not applicable.
Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.
Use of Large Language Models, AI and Machine Learning Tools: None declared.
Conflict of interest: All other authors state no conflict of interest.
Research funding: None declared.
Data availability: Not applicable.

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Received: 2024-10-16

Accepted: 2025-02-03

Published Online: 2025-02-25

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