Mechanisms underlying the role of gut-microbiota in biological sex-related differences in Alzheimer’s disease

• Applicant: Dr. Andrew Octavian Sasmita
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Molecular Biology and Physiology of Neurons and Glial Cells
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 555827182

Alzheimer's disease (AD) is the leading cause of dementia with pathological hallmarks that include the development of amyloid plaques, neurofibrillary tau tangles, and neuroinflammation. Additionally, the hippocampus – important for cognition and memory – undergo impairments in formation of new neurons (adult hippocampal neurogenesis, AHN) early in the disease. Despite advancements, treatment options are limited, and preventative measures do not exist against AD. Moreover, women are at a higher risk of developing AD compared to men, recapitulated by similar observations made in mouse models of AD. Although sex dimorphism in AD could easily be explained by hormonal differences, it remains under-researched. Here, we propose a project to investigate the involvement of the increasingly studied link between the gut microbiome on brain physiology. First, we will perform 16s sequencing of fecal and cecal matter from the 5xFAD mouse model of amyloidosis at different ages in both sexes. To expand our investigation, we will additionally perform a cecal and blood metabolomics screening to further probe for changes in the metabolome that can influence AHN, plaque deposition, and glial response in AD. Next, we will perform cross-sex fecal matter transplant (FMT) in 5xFAD mice to examine if sex differences in AHN, plaque pathology, and behavior could be modulated by FMT from another sex. Microbial or metabolite candidates with promising sex- and genotype-dependent distinctions will be orally administered to 5xFAD mice to investigate if they alone are sufficient to modify plaque deposition and AHN. Ultimately, the proposed experiments would allow us to better understand the gut-brain axis in the sex dimorphism seen in AD with therapeutic implications for FMT.

• DFG Programme: WBP Fellowship
• International Connection: Ireland
• Host: Professorin Dr. Yvonne Nolan