| Autor: |
Lars M. Ittner, Astrid F. Feiten, Bradley T. Hyman, Troy A. Butler, Amer Toutonji, Annika van Hummel, Yuanyuan Deng, Magdalena Przybyla, Julia van der Hoven, Carsten Krieg, Carol G. Au, Silvia Guglietta, Yazi D. Ke, Fabien Delerue, Fiona Bright, Susanne Wegmann |
| Rok vydání: |
2021 |
| Předmět: |
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| Popis: |
Background. Amyloid-β (Aβ) and tau form pathogenic lesions in Alzheimer’s disease (AD) brains. As ΑD clinically progresses, tau pathology propagates in a very distinct pattern between connected brain areas. The molecular mechanisms underlying this tau pathology spread remain largely unknown. Genome-wide association studies have identified polymorphisms in triggering receptor expressed on myeloid cells 2 ( TREM2 ) as genetic risk factors for AD and regulators of Aβ pathology-dependent tau propagation. Whether TREM2 contributes to neuron-to-neuron spreading of pathological tau remains unknown.Methods. Here, we crossed Trem2- deficient mice with P301S tau transgenic TAU58 mice and subjected the mice to behavioral testing and assessed neuropathology. Microglial activation states were determined using cytometry by of flight (CyTOF) and quantitative PCR. Tau spreading was assessed in vivo using tracing of focal tau expression.Results. Trem2 depletion significantly aggravated tau-induced early-onset motor and behavioural deficits. Neuropathologically, Trem2 reduction increased the number of hyperphosphorylated tau lesions in young TAU58 brains and reduced disease-associated microglia. Direct assessment of inter-neuronal spread of tau in vivo revealed significantly enhanced propagation of tau in the absence of Trem2 , suggesting that microglial TREM2 limits the progression of tau pathology in disease.Conclusion. Taken together, our data suggests that reduced TREM2 function accelerates the onset and progression of functional deficits and tau neuropathology in tau transgenic mice, which is - at least in part - due to increased tau spreading. Therefore, reduced TREM2 function may contribute to early AD by augmenting tau toxicity and its inter-neuronal propagation. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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