Role of pathologic isoforms of intracellular Aβ in neurodegeneration

The NeuroSchool PhD Program of Aix-Marseille University (France) has launched its annual calls for PhD contracts for students with a master's degree in a non-French university and for  international co-supervised PhDs.

This project is one of the proposed projects. Not all proposed projects will be funded, check our website for details.

State of the art - Despite significant efforts by the global scientific community to unravel the molecular mechanisms of Alzheimer’s disease (AD) over the past decades, the primary event triggering neurodegeneration remains elusive. Increasing evidence suggests that intracellular Amyloid-β (iAβ) plays a pivotal role in the early stages of AD development (Gallego Villarejo et al. 2022). Notably, iAβ directly interacts with another key protein implicated in AD—Tau (Zhang et al. 2021), which, in its hyperphosphorylated state, detaches from tubulin microtubules (MT), leading to their depolymerization. Recent findings indicate that iAβ facilitates Tau cross-seeding, further promoting its aggregation (Tripathi and Khan 2020). Additionally, several pathogenic mutations, such as those associated with the Tottori and English familial AD variants, along with specific post-translational modifications (e.g., Asp7 isomerization and Ser8 phosphorylation), have been shown to enhance Aβ aggregation, potentially exacerbating disease progression (Tsvetkov et al. 2008; Kozin et al. 2015; Kulikova et al. 2014).

Objectives - The primary objective of this PhD project is to elucidate the role of pathogenic forms of iAβ in the early stages of AD at the cellular level. Specifically, the study aims to investigate the impact of iAβ on its interaction with Tau, the subsequent aggregation processes, and their effect on MT stability. Methods - To achieve the objectives of this project, we will employ a combination of in vitro and cell-based approaches. The impact of pathogenic iAβ on its interaction with Tau will be investigated using ITC to quantify binding affinity and thermodynamics. The aggregation process will be studied using DLS, TEM, and ThS fluorescence to assess fibrillization and oligomerization. To evaluate the consequences of these events on MT stability and dynamics, we will analyze tubulin polymerization in vitro using DSF and turbidimetry. Additionally, cell-based colocalization experiments, including FRET microscopy, will be performed to investigate direct interactions between Tau, iAβ, and tubulin in cellular models.

Expected results - This project is expected to provide new insights into the role of pathogenic forms of iAβ in the early stages of AD. We anticipate clarifying how iAβ interacts with Tau, how this interaction influences Tau aggregation, and how these events affect MT stability and dynamics. Our findings should reveal whether specific mutations or post-translational modifications of iAβ enhance its pathological interactions with Tau, leading to MT destabilization. Furthermore, we expect to identify key molecular mechanisms underlying these processes, which may contribute to the development of new therapeutic strategies aimed at targeting intracellular amyloid-related toxicity in AD. 

Feasibility - The laboratory has all necessary equipment and extensive expertise in protein interactions, aggregation dynamics, and MT stability, ensuring the successful execution of the project. 

Within Aix Marseille Université, NeuroMarseille brings together 8 research laboratories and NeuroSchool, a graduate school in neuroscience, to increase the attractiveness of the university, international collaborations, interdisciplinarity, links with the clinical and industrial worlds and the integration of students into professional life. 

Launched in July 2018, NeuroSchool unifies and harmonizes the training of the third year of the Bachelor of Life Sciences (Neuroscience track), the Master's and the PhD in Neuroscience. 

• Master's degree from a non-French university in neuroscience or related field
• Fluent in English

The ideal candidate should be curious, proactive, and eager to learn, possess a good level in English or French, and demonstrate a willingness to develop expertise in both biophysical methods and cell-based experiments, along with good manual skills and attention to detail.