Journal of

Functional Morphology
and Kinesiology

Review
Physical Exercise and Health: A Focus on Its Protective Role in
Neurodegenerative Diseases
Roberto Bonanni 1 , Ida Cariati 1, * , Umberto Tarantino 1,2,3 , Giovanna D’Arcangelo 3,4
and Virginia Tancredi 3,4

1 Department of Clinical Sciences and Translational Medicine, “Tor Vergata” University of Rome,
00133 Rome, Italy; roberto.bonanni1288@gmail.com (R.B.); umberto.tarantino@uniroma2.it (U.T.)
2 Department of Orthopaedics and Traumatology, “Policlinico Tor Vergata” Foundation, 00133 Rome, Italy
3 Centre of Space Bio-Medicine, “Tor Vergata” University of Rome, 00133 Rome, Italy;
giovanna.darcangelo@uniroma2.it (G.D.); tancredi@uniroma2.it (V.T.)
4 Department of Systems Medicine, “Tor Vergata” University of Rome, 00133 Rome, Italy
* Correspondence: ida.cariati@uniroma2.it

Abstract: Scientific evidence has demonstrated the power of physical exercise in the prevention and
treatment of numerous chronic and/or age-related diseases, such as musculoskeletal, metabolic, and
cardiovascular disorders. In addition, regular exercise is known to play a key role in the context
of neurodegenerative diseases, as it helps to reduce the risk of their onset and counteracts their
progression. However, the underlying molecular mechanisms have not yet been fully elucidated. In
this regard, neurotrophins, such as brain-derived neurotrophic factor (BDNF), nerve growth factor
(NGF), glia cell line-derived neurotrophic factor (GDNF), neurotrophin-3 (NT-3), and neurotrophin-
4 (NT-4), have been suggested as key mediators of brain health benefits, as they are involved in
neurogenesis, neuronal survival, and synaptic plasticity. The production of these neurotrophic
Citation: Bonanni, R.; Cariati, I.;
factors, known to be increased by physical exercise, is downregulated in neurodegenerative disorders,
Tarantino, U.; D’Arcangelo, G.; suggesting their fundamental importance in maintaining brain health. However, the mechanism
Tancredi, V. Physical Exercise and by which physical exercise promotes the production of neurotrophins remains to be understood,
Health: A Focus on Its Protective posing limits on their use for the development of potential therapeutic strategies for the treatment of
Role in Neurodegenerative Diseases. neurodegenerative diseases. In this literature review, we analyzed the most recent evidence regarding
J. Funct. Morphol. Kinesiol. 2022, 7, 38. the relationship between physical exercise, neurotrophins, and brain health, providing an overview
https://doi.org/10.3390/ of their involvement in the onset and progression of neurodegeneration.
jfmk7020038

Academic Editor: Alessandro Keywords: physical exercise; brain health; synaptic plasticity; neurotrophins; neuroprotection;
Castorina neurodegeneration; preventive strategy

Received: 24 February 2022

Accepted: 27 April 2022
Published: 29 April 2022
1. Introduction
Publisher’s Note: MDPI stays neutral
Physical exercise is a non-pharmacological strategy for various disease conditions,
with regard to jurisdictional claims in
as well as for maintaining general health [1]. Numerous studies have shown that regular
published maps and institutional affil-
moderate-intensity physical exercise can bring enormous benefits to the entire body, revers-
iations.
ing at least some of the deleterious effects of a sedentary lifestyle and providing valuable
support for longevity [2–4].
The main benefits have been observed at the metabolic and cardiorespiratory level,
Copyright: © 2022 by the authors.
as physical exercise is known to promote better control of blood pressure and circulating
Licensee MDPI, Basel, Switzerland. cholesterol levels, a better ability of tissues, especially muscle tissue, to take up oxygen from
This article is an open access article the blood and remove carbon dioxide as a waste product, and a decrease in fat deposits,
distributed under the terms and especially visceral fat, which is mainly responsible for the onset of chronic diseases, such as
conditions of the Creative Commons metabolic syndrome, obesity, inflammation, and type 2 diabetes mellitus [5–9].
Attribution (CC BY) license (https:// Given the strong association of pathological conditions, such as hypertension with
creativecommons.org/licenses/by/ alterations in the blood-brain barrier and brain dysfunction, physical exercise may also
4.0/). have beneficial effects on cerebrovascular and cognitive functions, helping to delay brain

J. Funct. Morphol. Kinesiol. 2022, 7, 38. https://doi.org/10.3390/jfmk7020038 https://www.mdpi.com/journal/jfmk

J. Funct. Morphol. Kinesiol. 2022, 7, 38 2 of 18

aging and the onset of degenerative conditions, such as Alzheimer’s disease (AD) and
Parkinson’s disease (PD) [10,11]. In addition to improving cognitive and memory processes
by regulating the expression of growth factors and neurotrophins, physical exercise also
has a psychosomatic effect by promoting the release of endorphins, a particular group of
chemicals produced by the brain that have a powerful analgesic effect [12].
Finally, anti-inflammatory effects of physical exercise have been reported, which may
vary depending on the training protocol used. While a lifestyle with regular exercise,
compared to a sedentary lifestyle, can increase immune competence and reduce the risk
of infection, too intense and frequent training programs can have negative effects on
health [13,14].
In addition to being an effective preventive strategy, proper physical activity has
other benefits for the body, such as increasing muscle strength and elasticity, helping to
increase joint mobility, promoting flexibility, making movements more fluid, improving
coordination and balance, and reducing the risk of injuries and falls, especially for the
elderly [15].
Finally, adequate exercise can influence the metabolic health of an individual during
embryonic development [16]. Several clinical studies have shown that a mother’s physical
exercise during pregnancy not only improves brain maturation in newborns and, thereafter,
childhood language development, but also influences an offspring’s susceptibility to disease
in adulthood through fetal metabolic programming [17,18]. In this regard, Klein et al. have
recently shown that maternal exercise during pregnancy has long-lasting metabolic effects
on the offspring’s brain, particularly on mitochondrial function. Specifically, they observed
a neuroprotective role against β-amyloid (Aβ) neurotoxicity and cognitive impairment
in adulthood, and proposed maternal exercise as a promising strategy to delay or even
prevent the development of AD [19].
Thus, adopting an active lifestyle is undoubtedly one of the best strategies for prevent-
ing degenerative diseases, maintaining general health, and improving quality of life. In
this regard, the aim of our review was to investigate the impact of physical exercise on
brain health, summarizing the current knowledge on the underlying cellular and molecular
processes and highlighting how physical exercise may represent an effective alternative
strategy for preventing and/or counteracting neurodegeneration related to aging and/or a
sedentary lifestyle.

2. Literature Search Strategy

For this narrative review, 114 papers were selected from the Medline bibliographic
database, published between 1945 (starting date) and 2022. The selected papers included
studies of the impact of physical exercise on cellular and molecular processes under-
lying brain health and neurodegeneration. The search strategy was based on the use
and/or combination of the following keywords: “physical exercise”; “physical activity”;
“brain health”; “cellular mechanisms”; “molecular mechanisms”; “synaptic plasticity”;
“neurotrophins”; “neurodegeneration”; and “neuroprotection”. The search process was
performed on a worldwide basis, without excluding specific geographic areas or differ-
ent ethnic groups. Language filters and species filters were applied to the results list to
eliminate non-English articles.

3. Effects of Physical Exercise on Brain Health

In recent years, a growing body of scientific evidence has demonstrated the broad
effects of physical exercise on general brain health in animals and humans, especially
for learning and memory processes, protection from neurodegeneration, and alleviation
of depression [20,21]. Several mechanisms have been proposed to explain the influence
of physical exercise on brain function, particularly an exercise-dependent central and
peripheral regulation of several growth factors involved in neurogenesis, metabolism, and
vascular function. Accordingly, these factors may be responsible for the structural and
functional brain changes underlying synaptic plasticity [22].
J. Funct. Morphol. Kinesiol. 2022, 7, 38 3 of 18

3.1. Physical Exercise Improves Synaptic Plasticity

Synaptic plasticity, a fundamental property of neurons, consists of activity-dependent
changes in the strength and efficiency of synaptic transmission of pre-existing neuronal
connections [23]. These changes, which can last from a few milliseconds to hours or even
days, are primarily responsible for learning and memory processes, as well as for the
development of the brain’s response to injury [24]. Synaptic plasticity can result in a
persistent increase in synaptic strength, termed long-term potentiation (LTP), or a sustained
reduction in synaptic strength, known as long-term depression (LTD) [25].
Over the last 40 years, the phenomena of synaptic plasticity have been studied and
described in detail. However, the underlying molecular mechanisms are extremely complex
and the ways in which synaptic plasticity is induced in vivo or during learning, or altered
in neurodegenerative disorders, have yet to be fully explored [26].
Physical exercise is certainly one of the events that can induce synaptic plasticity.
Indeed, numerous studies on animal models have shown how regular exercise can improve
learning and memory processes and counteract age-related cognitive decline [27,28]. In this
regard, we recently evaluated the effects of an aerobic training protocol, administered three
times a week for twelve consecutive weeks, on the synaptic plasticity of 4-month-old mice
through electrophysiological recordings of hippocampal slices and ultrastructural analysis
of the hippocampus. In agreement with previous data [29], aerobic training not only
promoted an increase in synaptic plasticity compared to control mice, but also improved
hippocampal ultrastructure, as demonstrated by the complete structural conservation of
mitochondria, neurofilaments, and neurotubules, highlighting the effectiveness of aerobic
training in improving learning and memory processes [30].
The effects of physical exercise on brain health are most evident in mouse models
of aging, in which a recovery in cognitive function has been observed in active animals
compared to sedentary animals. Recently, Tsai et al. subjected young, adult, and old mice to
treadmill training and found a significant neuroprotective effect of exercise on age-related
brain changes, such as reduced dendritic length and branching and a decreased number of
spines in CA1 neurons [31]. Specifically, moderate-intensity treadmill running exercise for
6 weeks was reported to increase hippocampal synaptic plasticity and to preserve dendritic
complexity in all three experimental groups, as well as restoring learning and memory in
old mice [31]. Similarly, Li and colleagues assessed the effects of treadmill running for 6
days a week on cognitive function in mouse models of aging, observing an improvement
in spatial memory performance and a statistically significant reduction in pro-apoptotic
markers in the hippocampus [32]. Taken together, these observations suggest that aerobic
exercise plays a key role both in inducing the neuroplasticity involved in learning and
memory and in preserving learning and memory during aging by counteracting neuronal
death and cognitive decline in later life.
Notably, a significant improvement in synaptic plasticity was also observed after expo-
sure to whole body vibration (WBV) protocols, appropriately designed in terms of vibration
frequency, vibration exposure time, and recovery time between training sessions. In this
regard, we recently exposed 4-month-old mice to three different WBV protocols and, after
36 training sessions, assessed hippocampal synaptic plasticity using electrophysiological
recordings to determine which protocol was most effective in improving learning and
memory [33]. The WBV protocol, characterized by a reduced vibration exposure time and
a longer recovery period between two contiguous sessions, was observed to promote a
significantly better hippocampal response than control animals. Surprisingly, the same
WBV protocol administered to a group of 24-month-old animals resulted not only in a
marked improvement in synaptic plasticity, but also in the disappearance of signs related
to cognitive decline that characterized sedentary old mice [33]. Finally, beneficial effects of
WBV training have also been observed in middle-aged mice, including an improvement in
synaptic plasticity along with a significant increase in muscle fiber diameter and complete
preservation of cellular ultrastructure, suggesting vibratory training as a valid strategy for
delaying the onset of symptoms related to a sedentary lifestyle [34].
J. Funct. Morphol. Kinesiol. 2022, 7, 38 4 of 18

The beneficial effects of exercise have also been observed in humans, particularly
in elderly populations, as regular physical activity has been correlated with improved
memory processes and executive function in the brain, less age-related cognitive decline,
and greater protection from age-related atrophy in brain areas crucial for higher cognitive
processes [35]. Intervention studies in the elderly have demonstrated the effects of various
types of exercise, including endurance exercises, balance exercises, and gait retraining and
walking, on brain structure, function, and connectivity [36]. In particular, aerobic training
is known to increase the volume of grey and white matter in the prefrontal cortex of the
elderly, as well as increasing the volumes of the hippocampus and medial temporal lobe,
improving spatial memory and reducing the risk of cognitive impairment [37,38]. In this
regard, in a randomized controlled trial with 120 elderly people, Erickson et al. showed that
hippocampal volume loss in late adulthood is not inevitable, as a 1-year aerobic exercise
intervention was effective in increasing hippocampal volume by 2% and compensating
for the deterioration associated with aging [39]. Finally, new evidence suggests that the
combination of exercise and cognitive testing may increase the potential of prevention and
treatment programs to alleviate cognitive decline, confirming the key role of exercise for
longevity and more gradual aging [40,41].

3.2. Physical Exercise Improves Neurotrophins Production

Among the mediators responsible for the positive impact of physical exercise on
brain health, neurotrophins are undoubtedly the leading candidates, as they are involved
in numerous events that support structural and functional plasticity in the brain [42].
They are a heterogeneous and pleiotropic group of growth factors involved in a wide
number of biological functions, such as the growth and differentiation of new neurons
and synapses, the development of axonal and dendritic growth, synaptic plasticity, and
neuronal survival [43]. Neurotrophins are important regulators of adult neurogenesis,
a phenomenon that involves the formation of new neurons throughout life and occurs
in specific brain niches. Therefore, through the production of neurotrophins, physical
exercise could promote the preservation of cognitive functions and stimulate neurogenesis,
counteracting age-related cognitive decline [44]. Among the most studied neurotrophins
for which a neuroprotective role has been suggested, we focused our attention on brain-
derived neurotrophic factor (BDNF), nerve growth factor (NGF), glial cell line-derived
neurotrophic factor (GDNF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4), as shown
in Figure 1.

3.2.1. BDNF
BDNF is an essential neurotrophin that controls cognition, neuroplasticity, and an-
giogenesis, biological activities crucial in the development of learning and memory [45].
Numerous studies have reported that acute and chronic aerobic exercise increases circulat-
ing levels of BDNF in a manner dependent on the duration and intensity of exercise [46,47].
In particular, Azevedo et al. recently conducted a systematic review to assess the effects
of exercise on circulating BDNF levels in adolescents, finding that adopting an aerobic
exercise program was correlated with improvements in BDNF levels. Interestingly, the
greatest effects were found in groups of adolescents undergoing moderate- or high-intensity
exercise, confirming the dose-response effect that training might exert on neurotrophin
production [48]. Similarly, Coelho et al. observed that aerobic exercise, mainly of mod-
erate intensity, significantly increases circulating levels of BDNF in elderly individuals,
confirming the ability of aerobic exercise to modulate BDNF production [49].
J. Funct. Morphol. Kinesiol. 2022, 7, 38 5 of 18

Figure 1. Physical exercise promotes brain health through the production of neurotrophins. Neu-
rotrophins are growth factors with a protective role in the central nervous system. Among the most
studied are brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), glial cell line-
derived neurotrophic factor (GDNF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4), which are re-
leased following exercise and promote increased neurogenesis, myelination, and synapse number and
function, improve vascular health in the brain, and provide protection to the neuromuscular system.

Although the relationship between exercise and increased BDNF levels is well doc-
umented, the underlying biological mechanisms are not entirely clear. Studies in animal
models have shown that exercise increases the brain expression of BDNF, particularly
in the hippocampus. Among the proposed mechanisms, a key role could be played by
fibronectin type III domain-containing protein 5 (FNDC5), a protein expressed not only by
muscles during exercise, but also in the brain, as shown by the impaired neuronal devel-
opment observed in FNDC5 gene knockouts [50,51]. Interestingly, Wrann et al. showed
that exposure of mice to resistance exercise for 30 days induced not only a significant
increase in FNDC5 expression in the quadriceps muscle and hippocampus, but also in
hippocampal BDNF levels, suggesting a correlation between exercise-induced hippocampal
neurotrophin expression and FNDC5 expression. Although the underlying mechanism is
still unknown, exercise-induced activation of the peroxisome proliferator-activated receptor
gamma coactivator 1-alpha (PGC-1α)/FNDC5/BDNF pathway in the hippocampus has
been suggested to be potentially responsible for the positive regulation exerted by FNDC5
on BDNF expression [52].
β-hydroxybutyrate (DBHB), a ketone body whose levels are frequently increased
during caloric restriction and after prolonged exercise, was also proposed by Sleiman et al.
J. Funct. Morphol. Kinesiol. 2022, 7, 38 6 of 18

as a positive regulator of BDNF gene expression [53]. Specifically, DBHB treatment of

cortical neuron cultures and hippocampal slices from mice undergoing voluntary wheel
running was seen to induce an increase in BDNF transcription, compared to that of seden-
tary mice. According to the authors, this increase could depend on the involvement of
histone deacetylases (HDACs), a class of enzymes responsible for epigenetic modifications
that determine the regulation of gene transcription. Indeed, HDAC2 and HDAC3 are
known to inhibit BDNF gene expression, and treatment of primary neurons with DBHB
reduces the binding of HDAC2 and HDAC3 to BDNF promoters, thereby promoting their
transcriptional activation [53].
More recently, El Hayek et al. identified lactate as an endogenous metabolite, produced
during exercise, that can cross the blood-brain barrier and promote learning and memory
in a BDNF-dependent manner [54]. Specifically, the authors observed that male mice
subjected to 30 days of a running wheel showed higher hippocampal BDNF expression
than control mice, along with higher lactate levels, and that treatment of the mice with
intraperitoneal injections of a lactate transporter inhibitor abolished the expression of the
neuronal BDNF promoter. Interestingly, the involvement of sirtuin 1 (SIRT1), a class III
HDAC whose activity is dependent on the levels of high-energy molecules, was proposed
in the activation of the PGC-1α/FNDC5 pathway and BDNF expression, since repression
of SIRT1 expression by short non-coding RNA (shRNA) abolished lactate-mediated BDNF
expression in primary neurons [54].
Overall, these studies support the hypothesis that training is a potent inducer of
synaptic plasticity, as the production of particular metabolites during exercise can modulate
the activity of enzymes responsible for epigenetic modifications and activate the PGC-
1α/FNDC5 pathway, which is crucial for BDNF expression.

3.2.2. NGF
NGF is a growth, survival, and maturation factor of sympathetic and sensory neurons
involved in inflammatory hyperalgesia in adulthood. Indeed, its expression is known
to increase in skeletal muscle after ischemia and nerve injury, promoting sensitization of
sensory nociceptors [55]. In the central nervous system, NGF plays a neuroprotective role
through binding to tropomyosin receptor kinase A (TrkA) and p75 neurotrophin receptor
(p75NTR) [56]. This interaction promotes the activation of downstream pathways involved
in cell survival and differentiation, such as the phosphatidylinositol 3-kinase (PI3K)/protein
kinase B (Akt) signaling pathway. In addition, the activation of phospholipase C-γ (PLCγ)
by NGF induces intracellular calcium release and subsequent activation of specific calcium-
dependent proteins, ion channels, and transcription factors, all of which are crucial events
in neuroplasticity [56].
Recently, Wu et al. experimentally induced NGF overexpression in a hippocam-
pal neuronal cell line by taurine administration, observing an increase in TrkA and Akt
phosphorylation and, consequently, a significant reduction in apoptosis. The same NGF
expression changes were also observed after taurine administration in rats, in association
with an improvement in learning and memory, suggesting taurine as a potential candidate
against cognitive impairment through inhibition of hippocampal neuronal apoptosis [57].
Although several studies have confirmed the involvement of NGF in mnemonic
processes, its role in brain plasticity after physical exercise has not yet been well deter-
mined [58]. In this regard, Chae et al. studied the effect of moderate-intensity treadmill
exercise on NGF levels and the PI3K/Akt signaling pathway in the hippocampus of aged
rats, showing that training suppressed apoptosis by inducing Akt expression and increas-
ing NGF levels [59]. In agreement, Hong et al. observed increased NGF expression and
neuronal survival in the dentate gyrus of the hippocampus of rats subjected to 8 weeks of
treadmill exercise, confirming the role of neurotrophins in brain health [60].
Human studies have also found an increase in NGF levels in trained subjects. For
example, Bonini et al. compared the concentration of circulating NGF in pre-Olympic
athletes who were subjected to intense and prolonged exercise with that of healthy indi-
J. Funct. Morphol. Kinesiol. 2022, 7, 38 7 of 18

viduals, finding significantly higher values in the former group [61]. Moreover, Cho et al.
found a significant increase in resting concentrations of BDNF and NGF in obese Korean
women who underwent three 40-min sessions of aerobic treadmill exercise per week for 8
weeks, compared with a group of untrained women [62]. Interestingly, the exercise-induced
increase in NGF was reported to be intensity-dependent, as the same authors observed in a
group of 15 men undergoing treadmill running an increase in NGF of 12%, 19%, and 23%,
respectively, following low-, medium- and high-intensity exercise [63].
Although a large body of evidence suggests that exercise is responsible for the up-
regulation of NGF and subsequent improvement in cognitive function, the underlying
mechanism is not yet fully understood, highlighting the need for further studies to un-
derstand how this neurotrophin may contribute to the beneficial effects of exercise on
brain health.

3.2.3. GDNF
GDNF is a 134 amino acid protein originally identified for its ability to promote
dopamine uptake in midbrain dopaminergic neurons, ensuring their survival and dif-
ferentiation [64]. This neurotrophic factor performs its function through binding to the
rearranged during transfection (RET) receptor tyrosine kinase, in association with the
GDNF family receptor-α (GFRα). In particular, GDNF is known to initially bind to a GFRα
co-receptor and form a high-affinity complex that promotes the trans-phosphorylation of
specific tyrosine residues of the homodimeric RET receptor, initiating PI3K, extracellular
signal-regulated kinase (Erk), and Akt signaling, which are involved in cell survival [64].
Notably, GDNF has also been identified as the most potent neurotrophic factor for motor
neuron survival that can support and maintain the neuromuscular system, both during
development and in adulthood, promoting neuroplasticity [65].
Several studies have reported that exercise promotes GDNF expression, although
the molecular mechanism responsible for this effect is unclear. In 2013, McCullough
et al. evaluated the effect of two weeks of swimming or running exercise on the protein
content of GDNF in the spinal cord of young and old rats, finding a significant increase in
neurotrophins in the L1-L3 tract of the spinal cords of trained rats compared to sedentary
rats. In addition, trained animals showed an increase in the size of motor neurons and the
number of GDNF-containing vesicles, highlighting the effectiveness of short-term exercise
on GDNF expression [66]. Subsequently, Gyorkos and Spitsbergen hypothesized that
high-intensity exercise is effective in altering the protein content of GDNF and in inducing
neuromuscular junction plasticity (NMJ) [67]. The authors divided a total of 30 rats into
groups—two sedentary groups, two involuntary running groups, one at low and one at
high intensity, and two voluntary running groups, one with and one without resistance
—and assessed the expression and localization of GDNF in the slow twitch soleus muscle
and the fast twitch plantar muscle. The protein content of GDNF was increased by 174%
and 161% in the plantar muscle tissue of animals undergoing voluntary resistance training
and voluntary non-resistance training, respectively. For soleus muscle, there was a 145%
increase in GDNF levels in tissue from animals undergoing low-intensity involuntary
training, and a 272% increase in muscle from animals undergoing voluntary non-resistance
training. Thus, different exercise protocols can result in significant changes in GDNF
expression in different types of muscle tissue [67].
More recently, Peake et al. assessed changes in the expression of cytokines and neu-
rotrophins in a group of nine men subjected to lower body resistance exercise. Interestingly,
analysis of biopsies taken from the exercised leg both before exercise and after 2, 24, and
48 h showed an increase in the inflammatory infiltrate, mainly represented by neutrophils
and macrophages, together with a significant increase in NGF and GDNF levels, confirming
that the expression of these neurotrophins increases as a result of exercise [68].
Finally, an interesting feature of GDNF is its ability to perform retrograde transport
in motor neurons. In fact, this neurotrophin released from skeletal muscle can reach first
an axon terminal and then, following internalization, the cell body of motor neurons by
J. Funct. Morphol. Kinesiol. 2022, 7, 38 8 of 18

retrograde axonal transport, promoting their survival [69,70]. Thus, GDNF is responsible
for the survival of motor units and ensures the preservation of nerve and muscle function,
protecting the neuromuscular system.

3.2.4. NT-3 and NT-4

NT-3 is a protein of 257 amino acids, the expression of which begins during embryonic
development and gradually decreases in the postnatal period. In the adult brain, the
expression of NT-3 is confined to the dentate gyrus of the hippocampus, where it promotes
synaptic plasticity and enhances learning and memory [71]. In addition, NT-3 plays an
important role in the survival and function of sensory neurons, as well as in synaptic
transmission and maturation of the neuromuscular junction [72]. Exercise-induced NT-3
expression was observed by Koo et al., who assessed cognitive and motor recovery in a
group of rats with cortical injury induced by head trauma after exposure to wheel running
exercise for three weeks. Noteworthy, the reduction in NT-3 expression due to cortical injury
was restored in the trained animals, which also showed an improvement in motor function
and cognitive gain, suggesting a role for exercise-induced NT-3 in healing traumatic brain
injury [73]. In agreement, Hou et al. evaluated the effect of voluntary movement on NT-3
expression in neurologically impaired rats undergoing a cerebral ischemia-reperfusion
procedure by middle cerebral artery occlusion. Surprisingly, a significant reduction in
neurological deficits and a significant increase in NT-3 expression were found in trained
animals compared to sedentary ones [74].
Regenerative action has also been proposed for NT-4 by Chung et al., who observed a
reduction in its expression in the ischemic hemisphere of rats subjected to middle cerebral
artery occlusion. Interestingly, treadmill exercise increased the bilateral expression of both
the monomeric and dimeric forms of NT-4, as well as its receptor tyrosine kinase B (TrkB),
confirming the neuroprotective effect of exercise in improving brain function [75]. More
recently, Domínguez-Sanchéz et al. showed the results of a randomized clinical trial of 51
obese men divided into a sedentary group, a high-intensity exercise group, a resistance
training group, and a combined high-intensity and resistance exercise group. Analysis of
blood samples showed a significant increase in NT-3 and NT-4 levels in subjects undergoing
resistance and combined exercise, while higher but not significant values were observed in
subjects undergoing high-intensity training [76].
Together, this evidence supports the influence of physical exercise on the expres-
sion of NT-3 and NT-4, two important neurotrophins involved in neurogenesis, synaptic
transmission and plasticity, and cognitive recovery following brain injury. However, the
mechanisms by which exercise increases the expression of these neurotrophins still need
important investigation.

4. Physical Exercise as a Non-Pharmacological Strategy to Prevent Neurodegeneration

Physical exercise is generally indicated as the main non-pharmacological therapeutic
strategy for a wide variety of diseases, as shown in Figure 2. Indeed, regular exercise
can prevent and/or delay the onset of age-related diseases, such as osteoporosis and sar-
copenia, as well as metabolic and cardiovascular disorders [15,77]. In addition, numerous
scientific studies suggest that physical exercise can counteract the progression of a group
of nervous system disorders caused by amyloid deposits, known as neurodegenerative
diseases [78]. Although these diseases differ in their pathogenesis, symptoms and the area
of the brain initially affected, they share some interesting features, such as neurotoxicity
and the presence of insoluble plaques made up of aggregated protein material. Indeed,
a misfolding event has been proposed as the underlying mechanism that involves the
assumption by a specific protein of an incorrect conformation. This initial event causes
the misfolded proteins to aggregate into increasingly large species with a high neurotoxic
potential, leading to progressive neuronal loss in certain brain areas [79].
J. Funct. Morphol. Kinesiol. 2022, 7, 38 9 of 18

Figure 2. Beneficial effects of physical exercise. Physical exercise has a protective effect on a wide
variety of disease states, such as osteoporosis, sarcopenia, metabolic disorders, and cardiovascular
disorders. Physical exercise is also useful in counteracting the onset and progression of neurodegen-
erative diseases, including Alzheimer’s disease and Parkinson’s disease, by reducing the formation
of neurotoxic protein aggregates, such as β-amyloid protein plaques and lewy bodies. As a re-
sult, the protective action of physical exercise involves reducing neuroinflammation, mitochondrial
dysfunction, and cell death, and improving cognitive and motor functions.
J. Funct. Morphol. Kinesiol. 2022, 7, 38 10 of 18

Physical exercise, also through the release of neurotrophins, is an effective strategy

for preventing these pathologies, as it helps to preserve memory, neuroplasticity, and
neurogenesis.

4.1. Physical Exercise and AD

AD is a neurodegenerative disorder characterized by progressive memory loss and
inexorable cognitive decline caused by the accumulation of neurotoxic aggregates of the Aβ
protein and the phosphorylated protein Tau [80]. This disease is the most common cause
of dementia and affects around 30 million people worldwide [81]. Furthermore, recent
estimates have reported that, by 2050, the prevalence of the disease will double in Europe
and triple worldwide, highlighting the need to use all available tools to counter the onset
and progression of this disease [80].
Physical exercise has been suggested as a valuable treatment tool for preclinical and
advanced AD, as well as an effective prevention strategy, probably due to the ability
of physical exercise to improve cerebral blood flow, increase hippocampal volume, and
stimulate neurogenesis [82].
Recently, Hwang et al. evaluated the effect of regular moderate-intensity exercise on
improving cognitive function in a mouse model of AD [83]. Specifically, four groups of mice
were included: a control group; a group expressing human wild type presenilin-2 (PS-2), a
protein that when mutated determines the onset of AD; a group expressing mutated human
PS-2; and a group expressing mutated human PS-2 but subjected to treadmill exercise
50 min a day, 5 days a week, for a total of 6 weeks. Interestingly, the group of transgenic
animals subjected to exercise showed a greater aptitude for exploring new objects than
the untrained transgenic mice. Furthermore, transcriptomic analysis showed an increased
expression of factors associated with apoptotic death in the untrained mouse model of
AD, suggesting that regular exercise may reverse cellular abnormalities caused by Aβ
deposition [83].
Similar results have been observed in human studies in which elderly people diag-
nosed with AD underwent regular exercise to assess effects on cognition. For example,
Morris et al. evaluated the effect of aerobic training on the health of 76 individuals with
early AD randomized into two groups, one receiving aerobic exercise of 150 min per week
for 26 weeks and a control group receiving stretching exercises [84]. Aerobic exercise
promoted not only a modest gain in functional capacity, but also changes in cardiorespira-
tory fitness positively correlated with improved memory performance and an increase in
bilateral hippocampal volume, suggesting the protective role of aerobic exercise against
damage induced in the early stages of AD [84].
Although the mechanism by which exercise may counteract neurodegeneration has
not yet been fully elucidated, some neurotrophins produced during exercise appear to
play a crucial role in mediating this effect. For example, BDNF overexpression is known
to counteract AD memory loss in mouse models and non-human primates [85]. Indeed,
Aβ aggregates are responsible for reducing BDNF expression by downregulating the
cyclic adenosine monophosphate (cAMP) response element binding protein (CREB), a key
transcription factor for the expression of genes involved in synaptic plasticity and long-term
memory [86]. CREB activity is regulated by multiple kinase pathways, including PI3K/Akt,
protein kinase A (PKA), protein kinase C (PKC), which promote CREB activation through
phosphorylation, and glycogen synthase kinase 3 beta (GSK3β), which inactivates it. Aβ-
induced toxicity reduces CREB activity, either through inactivation of PKA or activation
of GSK3β, preventing the expression of genes involved in synaptic plasticity and BDNF
expression. This results in low BDNF in the hippocampus and cortex, brain areas involved
in higher cognitive functions, impairing memory and learning [87].
A further characteristic of AD is the loss of phenotype and function of basal forebrain
cholinergic neurons (BFCNs), whose trophic support is strictly dependent on NGF. An
alteration of NGF expression could be responsible for AD-induced BFCN atrophy. Indeed,
impaired conversion of the NGF precursor (proNGF) to the mature form (mNGF) was
J. Funct. Morphol. Kinesiol. 2022, 7, 38 11 of 18

frequently observed in AD brains, together with increased degradation of mNGF and

subsequent BFCN atrophy [88]. According to this “cholinergic hypothesis”, the dysfunction
of acetylcholine-containing neurons in the basal forebrain contributes significantly to the
cognitive decline typical of AD, suggesting a potential therapeutic role of NGF in preserving
the phenotype of these neurons [89]. However, the inability of NGF to cross the blood-brain
barrier, as well as the adverse effects induced by intraventricular administration, pose
difficulties regarding the use of this neurotrophin in AD treatment [90]. Interestingly,
intranasal administration of NGF in mouse models of the disease would appear to favor
the non-amylogenic pathway of amyloid precursor protein (APP) cleavage, thus reducing
Aβ formation [91].
A possible neuroprotective role has also been suggested for GDNF, whose serum
levels have been found to be significantly lower in AD patients [92]. Indeed, GDNF
overexpression by lentiviral vectors in mouse models of AD was found to be effective in
preserving memory and learning, while control animals showed significant cognitive loss.
Notably, the effect of GDNF upregulation was correlated with potent BDNF overexpres-
sion, suggesting a synergistic action for these neurotrophins in counteracting AD-induced
neurodegeneration [93].
Recent scientific evidence also indicates to a neuroprotective role for NT-3 in AD
progression, including the study by Yan et al., in which NT-3 overexpression in AD rats
was associated with improved cognitive function [94]. Specifically, transplantation of bone
marrow-derived mesenchymal stem cells (BMSCs) overexpressing NT-3 was shown to
promote neurorigeneration and cognitive gain in AD rats, pointing to β-catenin as a key
candidate responsible for this effect. β-catenin is an important member of the Wnt/β-
catenin signaling pathway and is mainly present in the cytoplasm. However, translocation
of β-catenin from the cytoplasm to the nucleus results in activation of downstream targets
that ultimately promote cell survival and proliferation. The authors demonstrated that
NT-3 can influence β-catenin expression, although the underlying mechanism remains
unclear [94].
Finally, Liu et al. observed the effect of NT-4 overexpression in the hippocampus of AD
rats, assessing changes in learning and memory. Specifically, grafting fibroblasts modified
with the NT-4 gene into the hippocampus of AD rats induced a significant survival of
cholinergic neurons in the host hippocampus and an equally significant preservation of
learning and memory functions [95].
Overall, the evidence reported suggests physical exercise as a surprising and effective
non-pharmacological strategy to counteract the cognitive decline that characterizes AD,
pointing to neurotrophins produced during exercise as key mediators in preserving higher
cognitive function and counteracting disease progression.

4.2. Physical Exercise and PD

PD is a degenerative neurological disorder characterized by the aggregation of the
protein α-synuclein (α-syn) in the form of lewy bodies, leading to the loss of dopaminergic
neurons in the substantia nigra [96,97]. It is the second most prevalent neurodegenerative
disease, with an annual incidence in high-income countries of 14 per 100,000 in the total
population and 160 per 100,000 in the over-65 population [98].
Despite the significant impact of PD on the elderly population, physical exercise
is currently the only valid primary prevention strategy able to reduce the risk of occur-
rence of the disease [98]. In this regard, Jang et al. evaluated the efficacy of resistance
exercise in a mouse model of PD experimentally induced by chronic injection of the neuro-
toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridin (MPTP) [99]. A total of 30 mice were
divided into a sedentary control group, an MPTP-treated group, and an MPTP-treated but
resistance-exercise group. At the end of the experimental period, a significant decline in
motor coordination was observed in the MPTP-treated mice, whereas the MPTP-treated
and resistance-exercise animals showed motor function comparable to that of the control
group. Interestingly, significantly lower levels of α-syn were found in mice receiving
J. Funct. Morphol. Kinesiol. 2022, 7, 38 12 of 18

resistance exercise, along with reduced expression of toll-like receptor 2 (TLR2) and nu-
clear transcription factor-κB (NF-kB), highlighting the ability of exercise to counteract both
the accumulation of neurotoxic aggregates and neuroinflammation and subsequent cell
death [99].
The efficacy of resistance exercise has also been observed in human clinical trials,
such as that of Schenkman et al., who enrolled a total of 128 subjects with PD, divided
into a high-intensity treadmill exercise group, a moderate-intensity exercise group, and a
control group. Interestingly, only the high-intensity exercise group reached the non-futility
threshold, as fewer motor changes were observed than in the usual care group, providing
evidence of the effectiveness of high-intensity exercise in treating PD patients [100].
BDNF and TrkB are known to be widely expressed in the dopaminergic neurons of
the substantia nigra, where they participate in the maturation and maintenance of neurons.
However, BDNF/TrkB expression is significantly impaired in PD patients, suggesting the
involvement of this neurotrophic factor in the PD pathogenesis [101]. Indeed, pathogenic
mutations in α-syn, which promote its aggregation and neurotoxicity, are associated with
a loss of BDNF and TrkB expression [102]. Furthermore, retrograde axonal transport
of BDNF/TrkB, which is essential for the growth and dendritic development of cortical
neurons, is impaired in the presence of α-syn fibrillar aggregates, leading to a deficit
in BDNF signaling and reduced transcription of specific nuclear targets [103,104]. The
reduced expression of BDNF as a molecular signature of PD has led to speculation about
its potential role as a therapeutic agent to treat the disease. However, direct administration
of exogenous BDNF has not shown significant and lasting improvements in the disease,
whereas treadmill exercise has been reported to increase BDNF and GDNF expression in
mouse models of PD [105,106]. Thus, physical exercise could exert its neuroprotective
action by upregulating various neurotrophins that would act synergistically to reduce the
neurodegeneration typical of PD.
NGF also shows an altered expression profile in PD subjects. Indeed, in 2002, Lori-
gados Pedre et al. detected significantly lower NGF levels in the serum of Parkinsonian
rats and individuals compared with control subjects [107]. Subsequently, Wu et al. demon-
strated for the first time that LLDT-67, a novel triptolide derivative, has a potent and specific
effect on NGF expression in astrocytes in vitro and in vivo, as it protects dopaminergic
neurons from MPTP-induced degeneration and stimulates neurotrophin expression, con-
tributing to its neuroprotective effects [108]. More recently, Luo et al. investigated whether
the caffeic acid derivative N-propargyl caffeamide (PACA) was able to increase NGF levels
against MPTP neurotoxicity in a mouse model of PD [109]. Interestingly, PACA not only
enhanced NGF-induced neurite outgrowth, but also improved motor disabilities in dis-
eased mice. Furthermore, PACA was found to increase the conversion of proNGF to active
NGF in the midbrain and to sequentially activate the PI3K/Akt, Erk, and CREB signaling
pathways, suggesting it as a potent drug candidate for the protection of dopaminergic
neurons against neurodegeneration in PD [109].
Regarding GDNF, its ability to promote the survival of nigrostriatal dopaminergic
neurons has suggested its possible use as a pharmacological agent in PD treatment. In
this regard, several clinical studies have been conducted to assess the efficacy of GDNF
administration by intracerebral injections in improving Parkinson’s symptoms or even
counteracting disease progression. The efficacy of GDNF was greater when infusion
was given into the putamen rather than the ventricles, which bodes well for the use of
neurotrophins as a therapy for PD. However, in other clinical trials, treatment with GDNF
was unsuccessful, raising doubts about its efficacy in treating PD [110,111]. Nevertheless,
the involvement of GDNF in PD has emerged in multiple trials. For example, Gottschalk
et al. recently evaluated the efficacy of oral administration of gemfibrozil, a drug approved
by the Food and Drug Administration (FDA) for the treatment of hypertriglyceridemia in
protecting dopaminergic neurons in a PD animal model. Notably, PD animals treated with
gemfibrozil showed improved motor activities in conjunction with increased transcriptional
activity of the GDNF gene in astrocytes [112]. Thus, the quality of impaired motor function
J. Funct. Morphol. Kinesiol. 2022, 7, 38 13 of 18

in PD could be closely related to optimal GDNF expression, although the role of this
neurotrophin in maintaining dopaminergic neurons needs further investigation.
Neural stem cell (NSC) transplantation has also been suggested as a promising re-
generative medicine therapy for the improvement of Parkinsonian symptoms. In this
regard, transplantation of rat neural stem cells endogenously expressing neurotrophin-3
(rNSC-NT3) into Parkinsonian rats treated with 6-hydroxydopamine (6-OHDA) by Gu et al.
was shown to improve their spatial learning ability and protect dopamine neurons in the
substantia nigra, reversing the main symptoms of PD [113]. Finally, Lingor et al. suggested
a synergistic action for NT-4 and GDNF in protecting dopaminergic neurons from damage
induced by oxidative stress, one of the main causes of cell death typical of PD, suggesting
the use of these neurotrophins for a possible therapeutic application [114].

5. Conclusions
Physical exercise is responsible for improving a wide variety of disease states, as well
as promoting brain health and preserving cognitive function. Numerous studies have
demonstrated the effects of predominantly aerobic exercise on synaptic plasticity, highlight-
ing a significant improvement in neuroplasticity phenomena associated with learning and
memory and a gain in motor function. An important role of physical exercise has been
observed especially for neurodegenerative diseases, as physical exercise is known to coun-
teract the progression of degenerative disorders affecting the nervous system and to reduce
the risk of their onset, preventing the cognitive and physical decline typical of age-related
diseases. This neuroprotective effect appears to be achieved by reducing the accumulation
of neurotoxic amyloid aggregates and reducing oxidative stress, neuroinflammation, and
neuronal death.
Neurotrophins have been suggested as one of the main mediators of this beneficial
effect, due to their ability to promote neuronal survival, development, and maintenance, as
well as neurogenesis and synaptic plasticity. The expression of neurotrophins is known to
be increased by physical exercise through mechanisms that may include the production of
specific metabolites and/or the activation of enzymes involved in epigenetic modifications
that regulate gene transcription. However, the underlying mechanisms are not yet fully
understood, placing limits on the use of neurotrophic factors in the development of potential
therapeutic strategies. Notably, neurotrophins could exert their beneficial power on brain
health and motor function through a synergistic action, which could be maximized by
physical exercise. Indeed, the role of skeletal muscle as an endocrine organ capable of
secreting a variety of neurotrophic factors with beneficial and neuroprotective effects is well
known. Therefore, it will be necessary to investigate the mechanisms by which neurotrophic
factors released not only by the brain, but also by skeletal muscle in response to exercise,
could act synergistically to ensure brain health and counteract the cognitive decline of
neurodegenerative diseases, including through the development of personalized exercise
protocols to achieve maximum neuroprotective action.

Author Contributions: Conceptualization, R.B. and I.C.; data curation, R.B. and I.C.; writing—original
draft preparation, R.B. and I.C.; writing—review and editing, U.T., G.D. and V.T.; supervision, U.T.,
G.D. and V.T. All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: No new data were created or analyzed in this study. Data sharing is
not applicable to this article.
Acknowledgments: The authors acknowledge Centre of Space Bio-medicine, “Tor Vergata” Univer-
sity of Rome for their support.
Conflicts of Interest: The authors declare no conflict of interest.
J. Funct. Morphol. Kinesiol. 2022, 7, 38 14 of 18

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