Tau aggregate composition and maturation in Alzheimer's disease

Alzheimer's disease (AD) is a devastating disorder that affects around 5% of the world population and there is no disease-modifying treatment capable of stopping the progression of the disease.The two main pathological hallmarks of AD are the appearance of senile plaques composed by extracellular β-amyloid (Aβ) aggregates and the presence of intracellular phospho Tau aggregates in the form of neurofibrillary tangles. During AD progression, Aβ and tau propagate throughout the brain in a hierarchical sequence. This development and spreading of both proteins starts during preclinical stages, long before symptoms are observed. Therefore, when Alzheimer's is diagnosed it can be already too late for a therapeutic intervention. Recently, the biochemical stages of Aβ aggregates maturation were established and associated with AD diagnosis and distribution of Aβ plaques in the brain (A. Rijal Upadhaya et al. (2014) Brain). In this study, it was clear that Aβ goes through a maturation process in which modifications in the protein structure occur, with the progressive appearance of novel forms of Aβ. On the other hand, although phosphorylation, aggregation and other post-translational modifications have been shown to play an important role in the formation of tau aggregates, it is not yet known when these alterations occur in the progression of the disease and whether the biochemical composition of tau aggregates influences their pathogenic potential.Therefore, this project will focus in the composition and maturation of tau aggregates throughout the pathogenesis of Alzheimer's disease. First, human brain samples from pre-clinical and symptomatic Alzheimer's disease cases will be extensively studied in terms of tau aggregates' compostion with the objective of establishing a sequence of events regarding Tau modifications. Furthermore, it will be investigated whether other proteins are differently associated with tau aggregates and whether these 'binding partners' play a role in the potential maturation proccess of tau aggregates. Finally, the pathogenic potential of tau aggregate maturation will be assessed by seeding experiments, in which specific fractions of the brain homogenates will be injected in transgenic mouse models. Thus, it will be tested whether the injected fractions are capable of inducing the onset of tau and/or Aβ pathology in these mouse models.

Jaar van publicatie:2021

Toegankelijkheid:Open