Alzheimer’s disease is a complex neurodegenerative disorder that starts long before the first symptoms appear. One of the earliest signs of AD is the accumulation of amyloid plaques and tau proteins in the brain, leading to neuronal death. AD is the leading cause of dementia worldwide, with the number of cases expected to reach 75 million by 2030.
Neuroinflammation plays a significant role in the development of AD. Microglia, cells that can both protect and damage the brain, are critical players in neuroinflammation:
- In the early stages of Alzheimer’s, microglia protect the brain by removing amyloid plaques and dead cells.
- In the later stages, microglia lose their protective function and produce pro-inflammatory cytokines, contributing to neuronal damage.
This makes microglia a therapeutic target in Alzheimer’s disease: enhancing the protective functions of microglia and reducing neuroinflammation with drugs and natural products can prevent disease progression.
The Role of Microglia in the Pathogenesis of Alzheimer’s Disease
Microglia are the brain’s immune cells, making up 10-15% of all glial cells. They are crucial in maintaining brain health, constantly scanning brain tissues and responding to environmental changes.
Depending on their state, microglia can both protect and damage the brain. In the aging brain and neurodegenerative diseases, microglia undergo significant changes. Disease-associated microglia (DAM) play an important role in Alzheimer’s disease. DAM helps destroy amyloid plaques and damaged neurons, but their functions can deteriorate over time.
LDAM (lipid droplet-accumulation microglia) is another type found in the aging brain, with a reduced ability to absorb and dispose of cellular debris (phagocytosis). LDAM produces high levels of reactive oxygen species and pro-inflammatory cytokines, leading to increased inflammation and neuronal damage.
Most of the Alzheimer’s disease risk genes are expressed in microglia. However, the role of microglia in AD is complex and contradictory. For example, the CSF1R protein in microglia is essential for developing, differentiating, and surviving myeloid lineage cells in the central nervous system. However, drugs blocking CSF1R improve cognitive functions in mice with Alzheimer’s disease.
Another vital protein in AD is the CX3CR1 receptor, which regulates microglial inflammatory responses. A deficiency in CX3CR1 reduces neuroinflammation and amyloid pathology but can worsen tau-related memory impairments.
Activated microglia can secrete exosomes containing tau protein, facilitating the spread of tau protein and accelerating the progression of Alzheimer’s disease. Hyperactivated microglia can also damage synapses, impairing neuron signal transmission and worsening cognitive functions.
Drug Treatment of Alzheimer’s Disease Related to Microglia
In 2021 and 2023, the U.S. Food and Drug Administration (FDA) approved Aducanumab and Lecanemab to treat Alzheimer’s disease. These drugs help reduce amyloid plaques in the brain, thereby slowing cognitive decline. Anti-Aβ immunotherapy targeting amyloid plaques activates microglia, which absorb amyloid plaques, reducing their toxicity.
Enhancing the Protective Functions of Microglia
Drugs that activate the TREM2 receptor on the surface of microglia are used to enhance the phagocytic capacity of microglia. TREM2 plays a crucial role in regulating inflammation, enhancing phagocytosis, and the survival of microglia. Drugs activating the TREM2 receptor strengthen the ability of microglia to clear amyloid plaques from the brain and show promising results in improving cognitive functions.
Other molecules and genes, such as CD33, CR1, and granulin, are also being studied for their influence on microglial function and Alzheimer’s disease development. CD33 is one of the susceptibility genes for Alzheimer’s disease. In the brains of Alzheimer’s patients, CD33 expression is significantly elevated in microglia and is closely associated with the formation of amyloid plaques. CD33 expression weakens microglial phagocytosis and promotes neuroinflammatory reactions. In mice with Alzheimer’s disease, deleting the CD33 gene increases the expression of anti-inflammatory genes, reduces amyloid plaques, and improves cognitive functions.
Increasing the copy number of the CR1 gene raises the risk of developing AD. The CR1 gene encodes a receptor that interacts with complement system proteins C1q, C3b, and C4b in microglia. Typically, microglia use complement-related signaling pathways to clear the brain of unnecessary and immature synapses. However, in Alzheimer’s disease, this process is disrupted, leading to synapse loss. Blocking C1q and C3 complement proteins in mice with AD helps prevent synapse loss and improve cognitive functions.
Granulin (GRN) is an essential protein in the later stages of Alzheimer’s disease. GRN helps regulate brain waste clearance, inflammation, damage repair, stress response, aging, and the health of nerve cells and microglia. If GRN levels in brain cells decrease, it increases amyloid plaques and memory impairment. Conversely, increasing GRN levels reduces amyloid plaques, prevents memory problems, and protects neurons.
MicroRNA-155 (miR-155) is a molecule that plays a significant role in the functioning of immune cells. Reducing miR-155 levels in the brain activates microglia, helping to condense amyloid plaques, improve neuronal nutrition, slow synapse destruction, and improve cognitive functions. Blocking interferon-γ signals weakens these positive effects, decreasing microglia’s performance potential. Therefore, miR-155 and IFN-γ may be promising targets for Alzheimer’s disease treatment.
Piezo1 is an ion channel in microglia that is sensitive to mechanical stimuli. Piezo1 responds to the stiffness of amyloid plaques and initiates calcium influx into cells, helping microglia gather around plaques and remove them. The absence of Piezo1 in microglia worsens amyloid pathology and reduces cognitive functions. Conversely, activating Piezo1 helps reduce plaque amounts and improve mental functions.
RIPK1 is a protein that is abundantly present in microglia in AD and impedes microglial phagocytic capacity. Blocking RIPK1 reduces neuroinflammation and amyloid plaques.
SYK is another essential protein in microglia that helps them absorb amyloid plaques. The absence of SYK promotes amyloid plaque formation and worsens cognitive functions. Activating SYK improves the brain’s clearance of plaques.
Reducing Neuroinflammation
Activated microglia produce pro-inflammatory cytokines TNF-α, IL-6, and IL-1β, which can lead to brain dysfunction. By controlling inflammation or enhancing anti-inflammatory responses, microglial activation can be managed to prevent the progression of Alzheimer’s disease (AD).
Nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, reduce inflammation, microglial activation, and the number of amyloid plaques in the brains of AD mice. However, clinical trials in patients with mild to moderate AD have not yet yielded convincing results.
The antibiotic minocycline has also shown promising results in mice, reducing inflammation and improving memory. Drugs blocking the pro-inflammatory cytokine TNF-α lower the risk of dementia in patients with inflammatory diseases and improve cognitive functions.
The P2X7 receptor, involved in inflammatory reactions, is associated with Alzheimer’s. Blocking P2X7 improves brain condition and behavior in mice at both early and severe stages of Alzheimer’s disease.
The inflammasome NLRP3 is a protein complex that activates inflammation. Blocking NLRP3 reduces inflammation, mitigates amyloid pathology, and improves cognitive functions in mice.
Targeting Toll-like receptors (TLRs) in microglial cells can help treat Alzheimer’s disease. In AD mice, suppressing TLR4 protects neurons and helps microglia transition to an anti-inflammatory state. Removing TLR4 enhances the microglia’s ability to clear amyloid plaques and shifts them from an inflammatory state to a protective one. Blocking TLR2 also reduces inflammation, improves brain condition, and preserves spatial memory in mice.
Anti-inflammatory molecules IL-10 and IL-4 play complex roles in Alzheimer’s disease. Reducing IL-10 levels decreases inflammation but worsens cognitive functions. Increasing IL-10 disrupts brain clearance of amyloid plaques and impairs cognitive behavior. Overexpression of IL-4 reduces inflammation but sometimes decreases microglial brain-clearing ability.
Conversely, the pro-inflammatory cytokine IL-6 enhances the microglial ability to remove amyloid plaques.
Natural Products for Alzheimer’s Disease Prevention and Treatment Affecting Microglia
Certain natural substances can protect nerve cells and reduce neuroinflammation. Antioxidant and anti-inflammatory compounds, including terpenoids, phenolic derivatives, alkaloids, glycosides, and steroidal saponins, reduce amyloid pathology in Alzheimer’s disease, lower neuroinflammation, and improve memory.
Gallic Acid: In green tea, walnuts, hazelnuts, grapes, blueberries, and bananas, gallic acid reduces neurotoxicity and inflammation caused by amyloid plaques.
Geniposide: Found in the fruits and roots of gardenia (Gardenia jasminoides), geniposide reduces inflammation and protects neurons by suppressing pro-inflammatory mediators (iNOS, TNF-α, IL-1β, and IL-6), increasing anti-inflammatory proteins (IL-10 and Arg-1), and stimulating the production of BDNF and glial cell line-derived neurotrophic factor (GDNF).
Goji Berries (Lycium barbarum): Used in traditional Chinese medicine, goji berries have shown promising results in improving brain condition in AD mice. The extract reduces neurotoxicity and inflammation, enhances neurogenesis, mitigates amyloid pathology, and improves cognitive functions.
NF-κB is a protein that regulates genes associated with inflammation and immunity. When amyloid plaques affect brain nerve and immune cells, NF-κB is activated, leading to neurotoxic effects and increased inflammation, which is observed in the brains of Alzheimer’s patients, where NF-κB activation exacerbates inflammatory reactions and contributes to disease progression. Several natural substances, including berberine (barberry, turmeric), loganin (medicinal dogwood), genistein (soy), ginsenoside (ginseng root), resveratrol (red grape skin, blueberries, cranberries), and hydroxysafflor (safflower flowers), reduce neuroinflammation and improve brain condition in AD by inhibiting NF-κB.
Conclusion
Microglia, the brain’s immune cells, play a crucial role in developing Alzheimer’s disease. Microglia can slow or accelerate AD progression by engulfing amyloid plaques and tau protein or promoting their spread and neuroinflammation.
Early detection and treatment of AD can significantly impact the disease’s course. Drugs that activate the protective functions of microglia and reduce neuroinflammation show promising results. Natural products with antioxidant and anti-inflammatory properties can also treat AD.
Improving microglial phagocytic capacity and reducing inflammatory responses can slow or prevent the progression of Alzheimer’s disease.
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Reference
Targeting Microglia in Alzheimer’s Disease: Pathogenesis and Potential Therapeutic Strategies
