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An Alzheimer's model to study the propagation of the pathological forms of tau

In an article published in Neurobiology of Disease, researchers from MIRCen's Neurodegenerative Diseases Laboratory present a novel model of Alzheimer's disease that enables the study of tauopathy inter-neuronal propagation mechanisms, the identification of new therapeutic targets and the exploration of new treatments.

Published on 16 June 2023

The pathological phenomena driving Alzheimer's disease result in the development of two characteristic histological lesions in the brains of patients: first, senile plaques, which are deposits of amyloid-β (a cleavage product of amyloid-beta precursor (APP) protein) in the extracellular matrix; and second, neurofibrillary tangles (NFTs), which are aggregations of hyperphosphorylated tau protein within neurons. "Tauopathy" is used to describe both the family of diseases involving NFTs and the NFTs themselves. These two typical lesions in Alzheimer's disease, senile plaques and NFTs, are always accompanied by neuroinflammation, itself characterized by astrocyte and microglia activation. Although many questions remain concerning the interplay between senile plaques, NFTs and neuroinflammation, it has become clear that the symptoms and symptom severity experienced by patients is largely tied to tauopathy propagation across anatomically connected cerebral regions. In Alzheimer's disease, tauopathy propagation follows a characteristic spatiotemporal course, ultimately invading the entire forebrain. To better understand tauopathy mechanisms and test new therapeutic strategies, pertinent and protean models able to recapitulate NTF propagation need to be developed.

Looking to do just that, researchers from the Cell-Cell Interactions in Neurodegenerative Diseases: Models and Biotherapies team within MIRCen's Neurodegenerative Diseases Laboratory determined that retinal ganglion cells (RGCs) were ideal for model construction. Indeed, the part of the central nervous system communicating with the retina is both affected by Alzheimer's disease and well characterized in terms of neuronal connections and anatomy. The researchers thus induced tauopathy in the RGCs via the overexpression of human, wild-type tau proteins. To do so, they employed recombinant adeno-associated viral (AAV) vectors, which have demonstrated their versatility for gene transfer in the central nervous system. Publishing their work in Neurobiology of Disease, the team first confirmed progressive neurodegeneration in the RBCs. They then applied their method in a TREM2-deficient murine model. In humans, TREM2 coding variants represent an important risk factor for Alzheimer's disease. The researchers showed that microglia activation contributes to RGC neurodegeneration, and very interestingly, that the artificial tauopathy only propagated to the target neurons in the superior colliculi (a midbrain structure) in older mice. Those findings suggest that factors associated with aging favor propagation of tauopathies across interconnected neurons.

Because of its pertinence and ease of use, the MIRCen team's model should continue to clarify tauopathy propagation mechanisms, help identify novel therapeutic targets and serve as a testbed for new treatments to slow or stop this important aspect of Alzheimer's disease.


Contact : Alexis ​Bemelmans

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