Engineered butyrate-producing yeasts mitigate Alzheimer-associated phenotypes

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease without effective treatments. 1 Extracellular amyloid plaques, neurofibrillary tangles, neuroinflammation, and neuronal loss are the characteristics of AD neuropathology. Amyloid β protein (Aβ), the major component of amyloid plaques, is produced through the sequential cleavage of the amyloid precursor protein (APP) by β-secretase BACE1 and γ-secretase. 1 Dysregulation of APP, BACE1, and γ-secretase increases Aβ generation while dysfunction of microglia reduces Aβ clearance, contributing to Aβ deposition. 2 The increase in Aβ deposition simultaneously activates microglia, promoting the secretion of a large number of pro-inflammatory cytokines. Dysregulation of gut microbiota and their metabolites plays a pivotal role in AD pathogenesis. 3 Among the metabolites, butyrate has beneficial effects on AD. Increasing the bioavailability of butyrate is critical for its clinical application. 4 To achieve consistent supplementation of butyrate, we have developed a strain of engineered butyrate-producing Saccharomyces cerevisiae (J17), a yeast probiotic, 5 which may mitigate AD phenotypes by the synergistic effect of butyrate supplementation and probiotic function of the chassis.