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Overview
This article explores the mechanisms by which senescent cells contribute to the onset and progression of Alzheimer's disease (AD). Alzheimer's disease is a common neurodegenerative disorder primarily affecting the elderly, characterized by progressive cognitive impairment and behavioral deficits. As the global population ages, the incidence of AD continues to rise annually, imposing a significant burden on society and families. Although significant progress has been made in AD research, the exact etiology and pathogenesis remain unclear. As one of the primary risk factors for AD, cellular senescence has garnered increasing attention in recent years for its role in the pathogenesis of AD. The accumulation of senescent cells in the body is closely associated with the onset and progression of various age-related diseases. Senescent cells play a crucial role in the pathological process of AD, and elucidating their mechanisms of action is of great significance for developing new treatments for AD.
Figure 1. Alzheimer's disease pathogenic proteins contribute to brain cell senescence. (a) Overview of the interaction between senescent brain cells with amyloid plaques and pathogenic tau. (b–e) Detailed view of each respective cell type and senescence-associated features reported in the literature: (b) neuron, (c) microglia, (d) oligodendrocyte/oligodendrocyte precursor cell, (e) astrocyte, and (f) blood-brain barrier (BBB) featuring endothelial cells, pericytes, and astrocytes, demonstrating compromised BBB integrity in AD.
Overview of Senescent Cells
(1) Definition and Characteristics of Senescent Cells
Senescence refers to the irreversible growth arrest of cells after undergoing a certain number of divisions or being exposed to various stress factors (such as oxidative stress, DNA damage, telomere shortening, etc.). Senescent cells exhibit unique phenotypic characteristics, including increased cell volume, flattening, and elevated β-galactosidase (β-gal) activity, which is a commonly used biological marker for identifying senescent cells. Additionally, senescent cells exhibit upregulation of cyclin-dependent kinase inhibitors (such as p16INK4a and p21Cip1), which inhibit cell cycle progression, causing cells to arrest in the G1 phase or G2/M phase and thereby preventing further division.
Mechanisms of Senescent Cell Formation
1. Oxidative Stress and DNA Damage: Oxidative stress is a key inducer of cellular senescence. Under normal physiological conditions, the production and clearance of reactive oxygen species (ROS) within cells are in dynamic equilibrium. However, with aging or under certain pathological conditions, increased ROS production leads to DNA damage. When DNA damage accumulates to a certain extent and cannot be effectively repaired, a series of signaling pathways are activated, such as the p53-p21 and p16-Rb signaling pathways, prompting cells to enter a senescent state. In brain tissue from Alzheimer's disease patients, oxidative stress levels are significantly elevated, leading to increased DNA damage in neurons and glial cells, which in turn induces cellular senescence.
2. Telomere shortening: Telomeres are repetitive DNA sequences at the ends of chromosomes that gradually shorten with cell division. When telomeres shorten to a certain length, they trigger senescence signals. In neural stem cells, telomere shortening is closely associated with the onset of senescence, which may impair the self-renewal and differentiation capacity of neural stem cells, thereby affecting the normal development and function of the nervous system.
The Mechanism of Action of Senescent Cells in Alzheimer's Disease
(1) Induction of Neuroinflammation
1. The Role of the Senescence-Associated Secretory Phenotype (SASP): Senescent cells exhibit a unique secretory phenotype known as the senescence-associated secretory phenotype (SASP). SASP comprises various cytokines, chemokines, growth factors, and proteases, such as interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor-α (TNF-α). In the brain tissue of Alzheimer's disease patients, senescent glial cells and neurons secrete large amounts of SASP factors, which can activate surrounding immune cells and trigger chronic inflammatory responses. IL-6 and TNF-α promote the activation of microglia, causing them to transition from a quiescent state to a pro-inflammatory state, releasing more inflammatory mediators and further exacerbating neuroinflammation. This chronic inflammatory environment damages neurons, impairs synaptic function, and leads to cognitive dysfunction.
2. Effects on glial cells: The aging of astrocytes and microglia plays a key role in AD neuroinflammation. Aging astrocytes secrete SASP factors that promote the aggregation and deposition of β-amyloid (Aβ) while inhibiting its clearance. The aging of microglia reduces their ability to phagocytose Aβ, preventing effective clearance of Aβ plaques in the brain. Instead, they release more inflammatory factors, creating a vicious cycle that exacerbates neuroinflammation and neurodegeneration.
Figure 2 Markers of cellular senescence are increased in brains of hTau mice modeling tauopathy of AD.
(2) Promotion of Neurodegeneration
1. Direct damage to neurons: Some cytokines and proteases secreted by senescent cells can directly damage neurons. Matrix metalloproteinases (MMPs) are one of the components of the senescence-associated secretome (SASP), which can degrade the extracellular matrix and neurotransmitter-related proteins, disrupting the structure and function of neurons. ROS produced by senescent cells can also cause oxidative damage to neurons, leading to neuronal apoptosis and death. In the brain tissue of AD patients, neuronal senescence is closely associated with cell death, which may be one of the key factors contributing to cognitive dysfunction.
2. Interference with Neurotransmitter Transmission: The presence of senescent cells may also disrupt the synthesis, release, and transmission of neurotransmitters. Inflammatory factors can inhibit the synthesis of acetylcholine, a neurotransmitter essential for maintaining normal cognitive function. Additionally, certain factors secreted by senescent cells may affect the expression and function of neurotransmitter receptors, leading to abnormal neurotransmitter signaling, further impairing communication and information processing between neurons, and thereby triggering cognitive impairments.
(3) Changes in Intercellular Communication
1. Abnormal Paracrine Signaling: Senescent cells communicate with surrounding cells through paracrine signaling by secreting SASP factors. These factors can affect the function and fate of neighboring cells, leading to disruption of the intercellular communication network. In the brain tissue of AD patients, SASP factors secreted by senescent glial cells can affect neuronal growth, survival, and differentiation, while also influencing the microenvironment of neural stem cells, inhibiting their proliferation and differentiation, thereby affecting neural regeneration and repair processes.
2.Disruption of intercellular connections: Senescent cells may also disrupt intercellular connection structures, such as tight junctions and gap junctions. In the blood-brain barrier, senescence of endothelial cells leads to reduced expression of tight junction proteins, increasing the permeability of the blood-brain barrier and allowing harmful substances to more easily enter brain tissue, exacerbating neuroinflammation and neurodegeneration. Gap junctions between neurons are crucial for the transmission of electrical signals and metabolic coordination between neurons. Factors secreted by senescent cells may disrupt the function of gap junctions, affecting synchronized activity and information transmission between neurons.
(4) Effects on the microenvironment of neural stem cells
1. Inhibition of neural stem cell proliferation and differentiation: Neural stem cells are present in the brains of adult mammals and have the ability to self-renew and differentiate into neurons, astrocytes, and oligodendrocytes. SASP factors secreted by senescent cells can alter the microenvironment of neural stem cells, inhibiting their proliferation and differentiation. Some cytokines in SASP can upregulate the expression of cyclin-dependent kinase inhibitors, causing neural stem cells to arrest at specific stages of the cell cycle and unable to undergo normal division and differentiation. Inflammatory factors secreted by senescent cells may also influence the differentiation direction of neural stem cells, causing them to differentiate more into glial cells rather than neurons, thereby affecting neural regeneration and repair.
2. Impact on neural stem cell migration: Neural stem cell migration is critical for their proper localization and functional activity within the brain. Certain factors secreted by senescent cells may interfere with neural stem cell migration, preventing them from migrating to areas requiring repair. Abnormal expression of chemokines may alter the migration direction of neural stem cells, preventing them from reaching the site of injury for repair, thereby impairing the nervous system's self-repair capacity.
Alzheimer's disease treatment strategies targeting senescent cells
(1) Senolytics
1. Mechanism of action: Senolytics are a class of compounds that can selectively eliminate senescent cells. Their mechanisms of action primarily include inducing senescent cell apoptosis and inhibiting senescent cell anti-apoptotic signaling pathways. Dasatinib and quercetin are currently the most studied combinations of senolytics. Dasatinib can inhibit the overactivated kinase signaling pathways in senescent cells, while quercetin enhances the effects of dasatinib. When used in combination, they can selectively induce apoptosis in senescent cells and reduce their accumulation in the body.
2.Progress in animal experiments and clinical studies: In animal experiments, treatment of AD model mice with senescent cell clearance agents significantly reduced the number of senescent cells in the brain, lowered neuroinflammation levels, and improved cognitive function. Studies found that after administering dasatinib and quercetin combination therapy to AD model mice, the amount of Aβ plaques in the brain decreased, neuronal damage was reduced, and spatial learning and memory abilities improved.
Figure 3 Cellular senescence as a component of healthy aging and AD.
(2) Senescence-associated secretory phenotype modulators (Senomorphics)
1. Mechanism of action: Senomorphics aim to regulate the secretion of SASP factors by senescent cells, reducing their harmful effects on surrounding cells. Some anti-inflammatory drugs can inhibit the expression and secretion of inflammatory factors in SASP, alleviating neuroinflammation. Some small-molecule compounds can regulate the metabolic pathways of senescent cells, altering the composition of SASP to weaken its damaging effects on surrounding cells.
2.Potential Application Prospects: The advantage of senescence-associated secretory phenotype modulators lies in their ability to improve the tissue microenvironment by regulating the secretory function of senescent cells rather than directly eliminating them. This may avoid some potential risks associated with senescent cell clearance agents, such as non-specific damage to normal cells. Therefore, senescence-associated secretory phenotype modulators hold broad application prospects and may emerge as a new therapeutic strategy for AD.
Conclusion
Senescent cells play a multifaceted role in the onset and progression of Alzheimer's disease. Through mechanisms such as inducing neuroinflammation, promoting neurodegeneration, altering intercellular communication, and influencing the microenvironment of neural stem cells, senescent cells exacerbate the pathological process of AD. Therapeutic strategies targeting senescent cells, such as the development of senescent cell clearance agents and senescence-associated secretory phenotype modulators, offer new options for the treatment of AD.
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