Microglial activation arises after aggregation of phosphorylated-tau in a neuron-specific P301S tauopathy mouse model

• Published in: Neurobiology of aging 2020-05, Vol.89, p.89-98
• Main Authors: van Olst, Lynn, Verhaege, Daan, Franssen, Marc, Kamermans, Alwin, Roucourt, Bart, Carmans, Sofie, Ytebrouck, Ellen, van der Pol, Susanne M.A., Wever, Dennis, Popovic, Marko, Vandenbroucke, Roosmarijn E., Sobrino, Tomás, Schouten, Marijn, de Vries, Helga E.
• Format: Article
• Language: English
• Subjects: Alzheimer's disease; FTD; Hyperphosphorylated tau; Microglia; P301S; Synapses
• ISSN: 0197-4580; 1558-1497
• DOI: 10.1016/j.neurobiolaging.2020.01.003

Alzheimer's disease, progressive supranuclear palsy and frontotemporal dementia are characterized by neuronal expression of aberrant tau protein, tau hyperphosphorylation (pTAU), tau aggregation and neurofibrillary tangle formation sequentially culminating into neuronal cell death, a process termed tauopathy. Our aim was to address at which tauopathy stage neuroinflammation starts and to study the related microglial phenotype. We used Thy1-hTau.P301S (PS) mice expressing human tau with a P301S mutation specifically in neurons. Significant levels of cortical pTAU were present from 2 months onwards. Dystrophic morphological complexity of cortical microglia arose after pTAU accumulation concomitant with increased microglial lysosomal volumes and a significant loss of homeostatic marker Tmem119. Interestingly, we detected increases in neuronal pTAU and postsynaptic structures in the lysosomes of PS microglia. Moreover, the overall cortical postsynaptic density was decreased in 6-month-old PS mice. Together, our results indicate that microglia adopt a pTAU-associated phenotype, and are morphologically and functionally distinct from wild-type microglia after neuronal pTAU accumulation has initiated. •pTAU aggregation precedes microglial activation in the cortex of PS mice.•PS microglia show morphological dystrophy, loss of homeostatic markers, and lysosomal swelling.•Lysosomal swelling of PS microglia coincides with both pTAU and postsynaptic spine engulfment.•Postsynaptic spine density is decreased in the cortex of PS mice.