Regional desynchronization of microglial activity is associated with cognitive decline in Alzheimer’s disease-Reference-Cited by-同舟云学术

Regional desynchronization of microglial activity is associated with cognitive decline in Alzheimer’s disease

Published:2024-09-05 Issue:1 Volume:19 Page:
ISSN:1750-1326
Container-title:Molecular Neurodegeneration
language:en
Short-container-title:Mol Neurodegeneration

Author:

Zatcepin Artem^ORCID,Gnörich Johannes,Rauchmann Boris-Stephan,Bartos Laura M.,Wagner Stephan,Franzmeier Nicolai,Malpetti Maura,Xiang Xianyuan,Shi Yuan,Parhizkar Samira,Grosch Maximilian,Wind-Mark Karin,Kunte Sebastian T.,Beyer Leonie,Meyer Carolin,Brösamle Desirée,Wendeln Ann-Christin,Osei-Sarpong Collins,Heindl Steffanie,Liesz Arthur,Stoecklein Sophia,Biechele Gloria,Finze Anika,Eckenweber Florian,Lindner Simon,Rominger Axel,Bartenstein Peter,Willem Michael,Tahirovic Sabina,Herms Jochen,Buerger Katharina,Simons Mikael,Haass Christian,Rupprecht Rainer,Riemenschneider Markus J.,Albert Nathalie L.,Beyer Marc,Neher Jonas J.,Paeger Lars,Levin Johannes,Höglinger Günter U.,Perneczky Robert,Ziegler Sibylle I.,Brendel Matthias

Abstract

Abstract Background Microglial activation is one hallmark of Alzheimer disease (AD) neuropathology but the impact of the regional interplay of microglia cells in the brain is poorly understood. We hypothesized that microglial activation is regionally synchronized in the healthy brain but experiences regional desynchronization with ongoing neurodegenerative disease. We addressed the existence of a microglia connectome and investigated microglial desynchronization as an AD biomarker. Methods To validate the concept, we performed microglia depletion in mice to test whether interregional correlation coefficients (ICCs) of 18 kDa translocator protein (TSPO)-PET change when microglia are cleared. Next, we evaluated the influence of dysfunctional microglia and AD pathophysiology on TSPO-PET ICCs in the mouse brain, followed by translation to a human AD-continuum dataset. We correlated a personalized microglia desynchronization index with cognitive performance. Finally, we performed single-cell radiotracing (scRadiotracing) in mice to ensure the microglial source of the measured desynchronization. Results Microglia-depleted mice showed a strong ICC reduction in all brain compartments, indicating microglia-specific desynchronization. AD mouse models demonstrated significant reductions of microglial synchronicity, associated with increasing variability of cellular radiotracer uptake in pathologically altered brain regions. Humans within the AD-continuum indicated a stage-depended reduction of microglia synchronicity associated with cognitive decline. scRadiotracing in mice showed that the increased TSPO signal was attributed to microglia. Conclusion Using TSPO-PET imaging of mice with depleted microglia and scRadiotracing in an amyloid model, we provide first evidence that a microglia connectome can be assessed in the mouse brain. Microglia synchronicity is closely associated with cognitive decline in AD and could serve as an independent personalized biomarker for disease progression.

Funder

Klinikum der Universität München

Publisher

Springer Science and Business Media LLC

Link

https://link.springer.com/content/pdf/10.1186/s13024-024-00752-6.pdf

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