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

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.

Metadata

Item Type:	Article
Authors/Creators:	Zatcepin, A. https://orcid.org/0000-0002-0224-088X Gnörich, J. Rauchmann, B.-S. Bartos, L.M. Wagner, S. Franzmeier, N. Malpetti, M. Xiang, X. Shi, Y. Parhizkar, S. Grosch, M. Wind-Mark, K. Kunte, S.T. Beyer, L. Meyer, C. Brösamle, D. Wendeln, A.-C. Osei-Sarpong, C. Heindl, S. Liesz, A. Stoecklein, S. Biechele, G. Finze, A. Eckenweber, F. Lindner, S. Rominger, A. Bartenstein, P. Willem, M. Tahirovic, S. Herms, J. Buerger, K. Simons, M. Haass, C. Rupprecht, R. Riemenschneider, M.J. Albert, N.L. Beyer, M. Neher, J.J. Paeger, L. Levin, J. Höglinger, G.U. Perneczky, R. https://orcid.org/0000-0003-1981-7435 Ziegler, S.I. Brendel, M.
Copyright, Publisher and Additional Information:	© 2024 The Authors. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
Keywords:	Alzheimer’s disease; Dementia; Microglia; Neuroinflammation; TSPO; PET; Brain connectivity; Microglia synchronicity; Microglia desynchronization
Dates:	Published: 5 September 2024 Published (online): 5 September 2024 Accepted: 20 August 2024
Institution:	The University of Sheffield
Academic Units:	The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > School of Medicine and Population Health
Depositing User:	Symplectic Sheffield
Date Deposited:	09 Sep 2024 10:36
Last Modified:	09 Sep 2024 10:36
Published Version:	http://dx.doi.org/10.1186/s13024-024-00752-6
Status:	Published
Publisher:	Springer Science and Business Media LLC
Refereed:	Yes
Identification Number:	10.1186/s13024-024-00752-6
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:216978

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

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