MICROGLIAL ACTIVATION DRIVES TAU PATHOLOGY PROGRESSION IN ALZHEIMER’S DISEASE

Alzheimer's disease (AD) is neuropathologically defined by the accumulation of amyloid-beta plaques, intracellular aggregates of phospho-tau and by a neuroinflammatory response driven by glial activation. The mechanisms that regulate the transition from presymptomatic to clinical AD remains unknown. The onset of cognitive decline is associated with the development of Tau pathology and coincides with alterations in the microglia-mediated innate immune responses. This supports the idea that AD is an Abeta-facilitated and microglial-dependent tauopathy leading to dementia. Here, we first evaluated the effects of TREM2 loss of function on microglial activity in a tauopathy transgenic mouse model (P301S). Using immunolabeling, electron microscopy and molecular techniques, we assessed different markers of microglial activation and neurodegeneration and performed quantitative evaluation of the tau pathology. Our analyses reveal a reduction in microglial activation in P301S/Trem2^KO mice compared to P301S controls, accompanied by a reduction in the Tau-laden pyramidal neurons and phospho-tau accumulation, along with associated neuropathological features. We confirmed that the microglial activation is the driven force that induces Tau pathology by pharmacological inhibition of these glial cells in the P301S tau model. Our results provide novel insights into the mechanistic link between microglial signaling ant tau pathology. Addressing the role of activated microglia on tau-related neurodegeneration may open new avenues for the development of therapeutic strategies aimed at modulating microglial functions to alter the clinical AD onset.
Supported by Instituto de Salud Carlos III PI24/00274(AG) and PI24/00308(JV) co-financed by FEDER Funds (European Union), Junta de Andalucía CTS950-G-FEDER(AG) and CIBERNED collaborative grant 2022-01(AG, JV).