TARGETING MICROGLIA TO MITIGATE TAU PATHOLOGY AND COGNITIVE DEFICITS IN A DOUBLE-TRANSGENIC APP-TAU MOUSE MODEL

The accumulation of Tau aggregates correlates strongly with cognitive decline in Alzheimer’s Disease (AD). Emerging evidence implicates microglia in synaptic loss, neurodegeneration, and the propagation of Tau pathology. Our study assesses the therapeutic potential of a microglial ADP receptor in modulating tauopathy progression. To this end, double-transgenic mice exhibiting both amyloid and Tau pathology were chronically treated with a pharmacological modulator of a microglial ADP receptor during either early or mild-advanced AD stages. Behavioural tests were performed to assess cognitive performance, while histological analyses were conducted to examine changes in microglial reactivity, Tau burden, and synaptic/neuronal loss. Our results indicate that pharmacological modulation of ADP receptor-mediated signalling altered microglial phagocytic activity and reduced the density of phosphorylated Tau+ neurons in the hippocampus. Crucially, treated mice exhibited preserved spatial memory in the Object Localisation Test compared to vehicle-treated controls. These findings suggest that modulating specific microglial purinergic signalling can interrupt the neurotoxic microglia-Tau crosstalk, highlighting a promising therapeutic target for modifying AD progression.
This work is being supported by Ministerio de Ciencia e Innovación (PID2021-125785OA-I00 and PID2024-161470OB-I00 funded by MICIU/AEI/10.13039/501100011033 and FEDER Una manera de hacer Europa, MP), Alzheimer Association (AARG-22-968879, MP), FI Grant (2024 FI-1 00935, YJ), and FPI Grant (PRE2022-102708 grant funded by MICIU/AEI/10.13039/501100011033 and by ESF+, UF).