What is already known
Alzheimer’s disease is a debilitating condition that causes memory loss and cognitive decline. The amyloid hypothesis proposes that the accumulation of beta-amyloid proteins in the brain damages nerve cells, but treatments targeting these proteins have shown limited success. However, recent research suggests that imbalances in gut bacteria and their by-products may influence brain inflammation and disease progression.
What this research adds
Working in a mouse model of Alzheimer’s disease, researchers found that specific bacteria such as Bacteroides ovatus reduce amyloid plaques, improve memory, restore synaptic function and reduce inflammation. Key to this effect is the compound lysophosphatidylcholine (LPC), which appears to protect brain cells by reducing oxidative stress and inhibiting ferroptosis — a form of cell death.
Conclusions
The findings suggest that gut microbes and LPC are potential therapeutic targets for Alzheimer’s disease.
Alzheimer’s disease is a debilitating condition that causes memory loss and cognitive decline, with the amyloid hypothesis suggesting that beta-amyloid protein buildup damages nerve cells. Now, research suggests that the gut microbiota play a crucial role in Alzheimer’s disease progression.
The findings, published in Cell Metabolism, suggest that gut microbes and some of their by-products are potential therapeutic targets for the condition.
So far, treatments targeting beta-amyloid proteins have shown limited success in treating Alzheimer’s disease, but recent studies have revealed a connection between the conditions and gut health. For example, bacteria such as Clostridium and Bacteroides have been linked to the accumulation of beta-amyloid. However, the exact changes in gut bacteria and how they influence the disease are still unclear.
To address this question, researchers led by Xu Zha at Capital Medical University in Beijing set out to study changes in the gut microbiota of a mouse model of Alzheimer’s disease.
Beneficial compound
Reducing gut bacteria with antibiotics lowered beta-amyloid plaque levels and improved memory, the researchers found. While gut bacteria such as Clostridium appeared to worsen plaque buildup, other microbes such as Bacteroides helped reduce it.
Treating the mice with Bacteroides ovatus reduced amyloid plaques, improved memory, restored synaptic function and reduced inflammation. Key to this effect was the compound lysophosphatidylcholine (LPC), which is produced when bacteria break down phosphatidylcholine — a type of fat molecule found in cell membranes.
B. ovatus, or a version of Escherichia coli engineered to produce LPC, dampened amyloid plaque buildup in mice, suggesting that the beneficial effects of phosphatidylcholine rely on the ability of gut microbes to produce LPC.
Therapeutic targets
Treating mice with LPC protected brain cells by reducing oxidative stress and inhibiting ferroptosis — a form of cell death. The treatment also improved the animals’ memory and reduced plaque buildup, the researchers found.
Further experiments showed that LPC reduces Alzheimer’s disease-related cell death by lowering the levels of ACSL4, a protein that promotes ferroptosis, and activating the GPR119 receptor, which in turn reduced ACSL4 levels and inhibited cell damage.
In people with Alzheimer’s, Bacteroides levels are reduced and Clostridium levels slightly increased, and blood levels of LPC are significantly lower compared to healthy individuals, the researchers found.
“These findings suggest that B. ovatus and LPC interventions hold promise as potential therapeutic avenues for [Alzheimer’s disease],” the authors say.
