The Therapeutic Potential of Butyrate and Lauric Acid in Modulating Glial and Neuronal Activity in Alzheimer's Disease

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by amyloid-β plaque accumulation, tau tangles, and extensive neuroinflammation. Neuroinflammation, driven by glial cells like microglia and astrocytes, plays a critical role in AD progression. Initially, these cells provide protective functions, such as debris clearance and neurotrophic support. However, as AD progresses, chronic activation of these cells exacerbates inflammation, contributing to synaptic dysfunction, neuronal loss, and cognitive decline. Microglia release pro-inflammatory cytokines and reactive oxygen species (ROS), while astrocytes undergo reactive astrogliosis, further impairing neuronal health. This maladaptive response from glial cells significantly accelerates disease pathology. Current AD treatments primarily aim at symptomatic relief, with limited success in disease modification. While amyloid-targeting therapies like Aducanumab and Lecanemab show some promise, their efficacy remains limited. In this context, natural compounds have gained attention for their potential to modulate neuroinflammation and promote neuroprotection. Among these, butyrate and lauric acid are particularly notable. Butyrate, produced by a healthy gut microbiome, acts as a histone deacetylase (HDAC) inhibitor, reducing pro-inflammatory cytokines and supporting neuronal health. Lauric acid, on the other hand, enhances mitochondrial function, reduces oxidative stress, and modulates inflammatory pathways, thereby supporting glial and neuronal health. Both compounds have been shown to decrease amyloid-β deposition, reduce neuroinflammation, and promote neuroprotection in AD models. This review explores the mechanisms through which butyrate and lauric acid modulate glial and neuronal activity, highlighting their potential as therapeutic agents for mitigating neuroinflammation and slowing AD progression.

Keywords: Alzheimer’s disease; astrocytes; butyrate; lauric acid; microglia; neurons.

Figure 1

Astrocytes and microglia in Alzheimer’s disease. This figure illustrates the dual roles of astrocytes and microglia in maintaining neuronal health under normal conditions and their detrimental contributions in response to Aβ pathology. In the healthy brain, astrocytes support synaptogenesis, synapse maturation, synaptic transmission, and metabolic processes while maintaining BBB integrity, water/ion homeostasis, neurotransmitter recycling, and phagocytosis. Conversely, microglia play neuro-supportive roles, including synaptic pruning, axonal projection shaping, and immune responses such as phagocytosis and cytokine production. Upon Aβ accumulation and the formation of senile plaques, astrocytes polarize into two distinct states: A1 astrocytes, which release pro-inflammatory cytokines (e.g., IL-6, IL-1β, TNFα) and neurotoxins, leading to neuronal and oligodendroglia death, and A2 astrocytes, which secrete anti-inflammatory cytokines (e.g., TGF-β, IL-10) and thrombospondin, promoting synaptic repair. Similarly, microglia exhibit dynamic responses; acute activation involves short-term cytokine release, enhancing Aβ clearance, and resolving inflammation. However, chronic activation, driven by prolonged Aβ exposure, results in excessive release of pro-inflammatory cytokines (e.g., IL-1β, TNF-α), impaired anti-inflammatory signalling (e.g., TGF-β, IL-10), reduced Aβ clearance, tau hyperphosphorylation, and NFT formation. This chronic state increases oxidative stress, impairs microglial motility, and disrupts neuroprotective functions, ultimately causing neuronal death and synaptic damage. Together, these processes highlight the critical balance astrocytes and microglia must maintain to support neural health and the devastating consequences when this balance is disrupted in neurodegenerative conditions.

Figure 2

Gut–Brain Axis and the inflammatory pathway. This figure highlights the interactions between the gut and brain in both healthy conditions and AD, focusing on the role of immune and microbial functions. In a healthy state, the brain exhibits minimal neuroinflammation, functional BBB integrity, ramified microglia, efficient myelination, and hippocampal neurogenesis support normal cognitive function. The gut maintains balanced immune cell activity, including dendritic cells, native T cells, and Th17 cells, producing IL-17 within the intestinal epithelium. A robust mucus layer supports a healthy microbial composition, which produces SCFAs that sustain proper metabolic function and immune regulation. In AD, disrupted communication between the gut and brain contributes to pathology. The brain experiences heightened neuroinflammation, elevated cytokine levels, BBB impairment, increased microglial activation, demyelination, reduced hippocampal neurogenesis, and cognitive decline. In the gut, immune function is disrupted, marked by altered dendritic cell activity, dysfunctional T cells, and excessive production of pro-inflammatory mediators like IL-17 and TNFα. The mucus layer is compromised, accompanied by an altered microbial composition and reduced SCFA production, leading to impaired metabolic functions. This bidirectional gut–brain dysfunction exacerbates neuroinflammation and disease progression, underscoring the critical role of the gut–brain axis in maintaining neurological health and its disruption in Alzheimer’s disease.