Jean-Pierre Roussarie

Early stages of classical amnestic Alzheimer’s disease (AD) specifically affect neurons from the layer II of entorhinal cortex (ECII). These neurons are crucial for assembling higher-order sensory information into new memories. The reason why they accumulate tau protein aggregates, why they dysfunction and degenerate faster than any other neuron type is a largely unexplored question.

Understanding what differentiates vulnerable from resistant neurons might open new therapeutic avenues, a necessity for the AD field. Vulnerability is a complex feature and likely results from a number of molecular pathways within ECII neurons, in addition to a particular neuronal and glial environment modulating these neurons. We have developed a framework combining cell-type specific profiling techniques, and systems-level functional genomics to identify the most salient properties of vulnerable ECII neurons (Roussarie, Yao et al. Neuron, 2020). As a proof-of-principle of our approach, we identified a proto-oncogene, DEK, which regulates both tau accumulation and neuronal excitability (Rodriguez-Rodriguez et al., bioRxiv, 2022). We now continue to explore vulnerability with this framework, to identify more drivers of neuronal vulnerability (which could become therapeutic targets) to gain insight into the different processes that regulate early stages of AD.

In addition, we are exploring the following directions:

– Comparing ECII neurons across species – humans are the only species with Alzheimer’s. Do human ECII neurons possess unique characteristics underlying this feature?

– Molecularly mapping the EC – in particular the various neuron subtypes within layer II, and the interneurons modulating them.

– Generating ECII neurons from human induced pluripotent stem cells in vitro.