Connecting microbiota and neurodegenerative diseases

Abstract

Alzheimer’s disease is a prevalent neurological disorder and the leading cause of dementia worldwide. Its main pathological hallmarks are amyloid plaques and neurofibrillary tangles which are accumulations of aggregated Abeta peptides and tau proteins respectively. Both proteins are present in non-pathological conditions. One of the main questions about the development of the disease is how these usually non-pathogenic proteins turn to the aberrant aggregation pathway leading to the disease. Although many factors have been studies it is still not fully elucidated._x000D_ _x000D_ This thesis investigates the Abeta aggregation behavior and the elements interfere with its aggregation. Firstly, we have studied its electrostatic properties by studying how pH and ionic strength alterations modify their aggregation. This way we have shown how localized changes of pH or ionic strength that occur in small compartments such as endosomes can create aggregative species which can be able to propagate faster than others formed at physiological conditions._x000D_ _x000D_ Secondly, we have studied how exogenous prion-like proteins derived from the gut microbiota can interfere with the Abeta peptides aggregation. This is important as the gut microbiota is a bacterial community present in our organism all along our life. This increases the probability of interactions between bacterial and human proteins which could have a negative impact on our health. In this study, we have seen how the microbiome has prion-like proteins capable of aggregating, acting like yeast prions and that are capable to cross-seed the amyloid beta peptides. Also, it has been seen that those proteins are toxic in human neuroblastoma cells and can cause a cognitive impairment in Caenorhabditis Elegans models. _x000D_ _x000D_ In conclusion, this study highlights several factors that can alter the aggregation of Abeta with exogenous prion-like proteins emerging as particularly concerning. Due to lifelong exposure to the gut microbiota, these proteins represent a potential risk factor in AD pathogenesis, as demonstrated by their capacity to drive aggregation and cognitive decline in model systems.

Date of Award	13 Oct 2025
Original language	English
Awarding Institution	Universitat Autònoma de Barcelona (UAB)
Supervisor	Natalia Sánchez Groot (Director)