Physical Exercise and Alzheimer's Disease: Effects on Pathophysiological Molecular Pathways of the Disease

Abstract

Alzheimer's disease (AD), the most common form of neurodegenerative dementia in adults worldwide, is a multifactorial and heterogeneous disorder characterized by the interaction of genetic and epigenetic factors and the dysregulation of numerous intracellular signaling and cellular/molecular pathways. The introduction of the systems biology framework is revolutionizing the study of complex diseases by allowing the identification and integration of cellular/molecular pathways and networks of interaction. Here, we reviewed the relationship between physical activity and the next pathophysiological processes involved in the risk of developing AD, based on some crucial molecular pathways and biological process dysregulated in AD: (1) Immune system and inflammation; (2) Endothelial function and cerebrovascular insufficiency; (3) Apoptosis and cell death; (4) Intercellular communication; (5) Metabolism, oxidative stress and neurotoxicity; (6) DNA damage and repair; (7) Cytoskeleton and membrane proteins; (8) Synaptic plasticity. Moreover, we highlighted the increasingly relevant role played by advanced neuroimaging technologies, including structural/functional magnetic resonance imaging, diffusion tensor imaging, and arterial spin labelling, in exploring the link between AD and physical exercise. Regular physical exercise seems to have a protective effect against AD by inhibiting different pathophysiological molecular pathways implicated in AD.

Keywords: Alzheimer’s disease; amyloid-β peptide; molecular pathways; physical exercise; tau protein.

Figure 1

Alzheimer’s disease and related molecular pathways.

Figure 2

Immune system and inflammation pathway in AD. In AD, the accumulation of Aβ plaques (step 1) causes activation of microglia resulting in synaptic phagocytosis (step 2) and therefore neurodegeneration. This creates a self-perpetuating cycle (step 3) that increases neurodegeneration and induces a state of chronic neuroinflammation. Abbreviations: Aβ, amyloid beta; AD, Alzheimer’s Disease.

Figure 3

Endothelial function and cerebrovascular insufficiency pathway. In AD brains, the neuroinflammatory response causes an increase in the blood brain barrier (BBB) permeability. Also, the deposition of Aβ plaques in cerebral vessels (step 1) can augment BBB permeability (step 2), resulting in a release of peripheral inflammatory mediators on the brain, increasing the oxidative stress. This potentiates the self-perpetuating cycle of AD pathogenesis. Abbreviations: Aβ, amyloid beta; AD, Alzheimer’s Disease.

Figure 4

Apoptosis and cell death pathway. In the intrinsic pathway, the interaction of Aβ plaques with surface receptors of the neuron (step 1) results in ROS generation and expression of caspases and proapoptotic genes. In the extrinsic pathway Aβ produces a stimulus resulting in the activation of caspases. Both pathways produce an increase in mitochondrial permeability (step 2) and provokes the neuronal apoptosis (step 3) and therefore the activation of the self-perpetuating cycle (step 4). Abbreviations: Aβ, amyloid beta; Apaf 1, apoptotic protease-activating factor 1; CD95, cluster of differentiation 95; CytC, cytochrome C; H₂O₂, hydrogen peroxide; O₂⁻, oxide; ROS, reactive oxygen species; t-Bid, truncated bid protein; TNF, tumor necrosis factor.

Figure 5

Intercellular communication within nervous system pathway. In AD, the accumulation of Aβ in the surface receptors (step 1) and the synaptic spaces (step 2) causes a reduction in neurotransmitter levels, impeding the recapture of these (step 3) and increasing the phosphorylation of tau protein and the creation of Aβ plaques inside the axon. Abbreviations: 5-HIIA, 5-hydroxy indoleacetic acid; 5-HT, 5-hydroxytryptamine or serotonin; Aβ, amyloid beta; Acetyl-CoA, acetyl coenzyme-A; Ach, acetylcholine; AChE, acetylcholinesterase; APP, amyloid protein precursor; BDNF, brain-derived neurotrophic factor; Ca²⁺, calcium ion; CHT1, high-affinity choline transporter 1; CoA, coenzyme-A; MAO-A, monoamine oxidase A; Na⁺, sodium ion; TPH2, tryptophan hydroxylase 2; Trp, tryptophan; SERT, serotonin transporter.

Figure 6

Metabolism, oxidative stress and neurotoxicity pathway. Abnormal accumulation of Aβ plaques, loss of mitochondrial function, increased production of ROS, metal dyshomeostasis, and diminished antioxidant protection mechanisms are all occurring during the progression of AD pathophysiology. Mitochondria participate in multiple cellular/molecular activities, such as energy metabolism, ATP synthesis, Ca²⁺ signaling, and iron (among other metals) homeostasis. Therefore, neuronal viability is greatly dependent on mitochondrial activity. Thus, mitochondrial deficiencies are frequently detected in neurodegenerative diseases, including AD. Since mitochondria are the primary source of ROS, any abnormality in the proper function of the electron transport chain results in damage of a number of biomolecules (i.e., proteins, lipids, nucleic acids). In patients with AD, Aβ accumulation is associated with impairment of mitochondrial activity, decreased oxidative phosphorylation, and ROS generation. As a result, a reduction of energy supplies is observed. In AD brains, ROS levels are significantly more elevated than in healthy brains. During the generation of Aβ plaques, several ROS species are produced; particularly, H₂O₂ is one of the most relevant ROS species. The ROS/H₂O₂ production further triggers production and aggregation of Aβ, which, in turn, can lead to ROS/H₂O₂ generation. Bidirectional interactions between ROS and Ca²⁺ signaling pathways are typical: ROS is able to modulate cellular Ca²⁺ signaling, which in turn is crucial for ROS production. Hence, increased levels of Ca²⁺ activate the enzymes responsible for the creation of ROS and free radicals. The ROS-Ca²⁺ interplay participates in several pathophysiological conditions, for instance AD, Parkinson’s disease, inflammatory diseases, and cancer. AD patients also show altered homeostasis of metals, including iron, copper, or zinc, that damages the cell redox system and promotes oxidative load as well as an increased deposition of extracellular Aβ plaques. Oxidative load induces the production of elevated amounts of end-products of lipid peroxidation, various different oxidized proteins, and oxidative alterations in both nuclear and mitochondrial DNA. Abbreviations: Aβ, amyloid beta; AD, Alzheimer’s disease; Ca²⁺, calcium; H₂O₂, hydrogen peroxide; ROS, reactive oxygen species.

Figure 7

DNA: damage and repair pathways. The deposition of Aβ peptides (step 1) can difficult the non-homologous end junction repair (step 2) leading to the accumulation of numerous lesions of DNA, resulting in apoptosis and ROS generation (step 3). This can activate the self-perpetuating cycle of AD. Abbreviation: Aβ, amyloid beta; AD, Alzheimer’s disease; DNA, deoxyribonucleic acid; ROS, reactive oxygen species.

Figure 8

Cytoskeleton and membrane proteins pathway. The neurotoxicity induced by tau protein is associated with an increase in actin filament levels (step 1) and cytoskeleton remodeling, causing plasma membrane blistering and more neurotoxicity (step 2). Also, a reduction in the dynamism of microtubules is caused by the sequestration of MAP2 by a modified tau protein. Abbreviations: Aβ, amyloid beta; MAP2, microtubule-associated protein 2; nm, nanometers.