Abstract
Neurodegenerative diseases (NDs) are a group of disorders characterised by the progressive loss of neurons in the central or peripheral nervous system. The most common NDs include Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease, and amyotrophic lateral sclerosis (ALS). With ageing being the primary risk factor, the prevalence of NDs poses a severe threat to elderly health and brings a heavy socioeconomic burden, while effective therapeutic strategies remain limited.
Traditional Chinese medicine (TCM), with its multi-target, multi-pathway and synergistic effects, has shown significant potential in managing NDs. Ganoderma lucidum (Lingzhi), also known as the “mushroom of immortality,” has been used in China for more than 2,000 years. Modern pharmacological studies have revealed that its major bioactive components, including polysaccharides and triterpenoids, exert neuroprotective effects by inhibiting neuronal apoptosis and damage.
AD, the most prevalent type of dementia, is pathologically characterised by extracellular amyloid-β (Aβ) plaques and intracellular neurofibrillary tangles formed by abnormally phosphorylated Tau proteins. Extracts and active constituents of G. lucidum have demonstrated the ability to alleviate AD pathology through several mechanisms.
Mechanisms of G. lucidum in the Prevention and Treatment of AD
1. Inhibition of Aβ Production and Deposition
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G. lucidum ethanol extract upregulates methylation regulators, reducing neuronal apoptosis, brain atrophy, and Aβ1-42 accumulation.
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Ganoderic acid A (a triterpenoid) activates the Axl/Pak1 pathway to promote autophagy in microglia, enhancing Aβ42 clearance and improving cognitive function.
2. Suppression of Tau Protein Hyperphosphorylation
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Broken G. lucidum spore powder inhibits NLRP3 inflammasome activation, reducing inflammatory cytokines and Tau hyperphosphorylation.
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GLT (Ganoderma lucidum triterpenes) decrease phosphorylated Tau and Aβ levels in AD models, regulate NF-κB signalling, and promote autophagy gene expression (LC3A/B), thereby preserving neuronal integrity.
3. Attenuation of Neuroinflammation
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Ganoderic acid A (GAA) inhibits LPS-induced microglial activation, shifting cells from pro-inflammatory (M1) to anti-inflammatory (M2) states, reducing IL-1β, IL-6, and TNF-α, while promoting brain-derived neurotrophic factor (BDNF).
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G. lucidum polysaccharides (GLP), such as GL70 and GLP70-1-2, modulate TLR4/MyD88/NF-κB signalling, lowering pro-inflammatory cytokines and improving learning and memory in AD models.
4. Protection Against Oxidative Stress
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GLP reduces ROS-induced neuronal apoptosis by downregulating Caspase-3, Bax, and Bim, while upregulating anti-apoptotic Bcl-2.
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This prevents oxidative stress–induced neuronal injury, highlighting the antioxidative neuroprotective potential of G. lucidum.
5. Enhancement of Synaptic Plasticity
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GLP promotes neural progenitor proliferation and improves cognition in AD mice by activating fibroblast growth factor receptor 1 (FGFR1) and its downstream ERK signalling.
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This supports synaptic growth and plasticity, crucial for memory and cognitive function.
6. Regulation of the Cholinergic Nervous System
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G. lucidum extract cultivated on germinated brown rice exhibits acetylcholinesterase (AChE) inhibitory activity.
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Administration enhances antioxidant enzyme activity, increases phenolic and flavonoid content, reduces free radical–induced neuronal damage, and preserves cholinergic neurotransmission.
Summary
In conclusion, extracts and active compounds of Ganoderma lucidum contribute to AD prevention and treatment via six major mechanisms:
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Inhibiting Aβ production and deposition
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Suppressing Tau hyperphosphorylation
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Reducing neuroinflammation
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Protecting against oxidative stress
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Enhancing synaptic plasticity
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Regulating the cholinergic system
These findings provide valuable insights into the potential of G. lucidum as a natural therapeutic agent for AD and other neurodegenerative disorders.