Deciphering the role of sodium butyrate on the enteric nervous system and microglia phenotype in Alzheimer’s disease models

Alzheimer's disease (AD) is a neurodegenerative disorder that affects approximately 44 million people worldwide, which makes it the most prominent form of dementia. AD research has been focused on the central nervous system (CNS) for long, but in recent years, the intestinal tract gained more attention. AD, like many neurological disorders, is associated with a variety of GI symptoms, raising the possibility that the enteric nervous system (ENS) could also be affected, simultaneously with the dysbiosis, observed in AD patience. Supporting this idea, an early report showed that plaques immunoreactive for Aβ could be found in the submucosa of AD patients. Amyloid precursor protein (APP), from which Aβ is derived, is normally expressed by enteric neurons and glia, making it further plausible that AD pathophysiology could involve the ENS. Moreover, it is pointed that ENS undergoes significant changes during the early onset of AβPP expression in AD mouse models that appear before those seen in the brain. AD pathology includes severe shifts in microbiota composition. The abundant butyrate-producing genera decreased significantly. SCFAs, particularly butyrate, have several protective features such as maintenance of the integrity of the intestinal wall, tight junction amplification and maintaining the balance of the inflammatory pathways. Butyrate suppresses production of the bacterial LPS-induced pro-inflammatory cytokines, IL-1, IL2, IL6, IL8, IL12, and TNFα by blocking the NF-κB transcription factor in dendritic cells. To support such connection, one clinical study focusing on the association between SCFA concentration and AD disease burden suggested a correlation between amyloid load and blood SCFA concentrations. In addition to the immunomodulatory features, SCFAs have been shown to regulate the protein-protein interactions between Aβ1-40 and Aβ1-42 peptides, thus impeding the assembly of neurotoxic Aβ aggregates. In contrast to that, it was shown that SCFA supplementation to GF AD mice increased the Aβ plaque load, this was accompanied by the pronounced alterations in microglial transcriptomic profile, including upregulation of ApoE. Taken together, contradictions in existing studies provoke the question how the butyrate influences on the cells of enteric nervous system and how it can modulate microglia state in Alzheimer’s disease model.
In this project, we will study the effect of diet on cognition and the effect on the brain in mice. We will specifically look into how the risk factor for AD, the protein ApoE 3 and ApoE4, can be affected by the diet and the cognition, as well as other gene expression and histological changes in the brain.