Co-pathologies, 2025-2028

Project: Astroglial ApoE as a mediator of β-amyloid pathology in synucleinopathies

Funded by the HFRI, 2025-2028

Principal Investigator: Leonidas Stefanis, BRFAA
Main Collaborator: Era Taoufik, Pasteur Institute
Additional Collaborators: Spiros Efthimiopoulos, NKUA; Markus Zweckstetter, Univ of Gottingen; Ronald Melki, CNRS, Universite Paris-Saclay; Tony Wyss-Coray, Stanford University

Co-pathologies, meaning the deposition of multiple types of aggregated proteins, are a recognized feature in neurodegenerative diseases. It has become clear that co-pathologies enhance the primary neurodegenerative process and lead to accelerated disease progression, hence it is very important to understand the underlying mechanisms in order to devise appropriate treatments.  This project, funded by the HFRI, seeks to decipher the origin of Alzheimer-type co-pathologies, and in particular β-amyloid deposition, in Lewy Body Diseases (Parkinson’s Disease and Dementia with Lewy Bodies), which are characterized by aberrant deposition of α-synuclein in the nervous system. The working hypothesis is that such co-pathology arises, at least in part, through the intermediary action of astroglial cells that secrete ApoE, which then in turn, in a genotype-dependent fashion, impacts amyloidogenic pathways in neurons. Initial data (see Figure 3 below) support this hypothesis.
The project will use both cell culture and in vivo models to examine this hypothesis.  Cell culture experiments will be performed in rodent and human models, including human iPSC-derived neurons and astroglia. Cultured astroglia will be exposed to aberrant forms of α-synuclein, including conditioned medium from iPSC-derived neurons generated from carriers of the p.A53T SNCA mutation, and will be examined regarding the induction of ApoE and other related pathways, such as the TGF-β pathway. A more open-ended approach will also be utilized to decipher other possible alterations, using transcriptomics and secretomics.  We will then examine the impact of various forms of ApoE and other factors secreted from aberrant α-synuclein-exposed astrocytes on neuronal homeostasis, in particular regarding amyoidogenic pathways, and the mechanisms involved.  Lastly, we will examine whether ApoE-, TGF-β-and β-amyloid-related pathways are activated in vivo in a transgenic mouse model of synucleinopathy. 
The project involves a multi-disciplinary team from BRFAA and the Pasteur Institute (see picture) and additional collaborators, with expertise in imaging, -omics approaches, glial and neuronal biology, and cell culture and animal models of synucleinopathy, including iPSC-derived neural cells from carriers of the prototypical p.A53T SNCA mutation, linked to familial Parkinson’s Disease.