TY  - JOUR
AU  - Zatcepin, Artem
AU  - Gnörich, Johannes
AU  - Rauchmann, Boris Stephan
AU  - Bartos, Laura M
AU  - Wagner, Stephan
AU  - Franzmeier, Nicolai
AU  - Malpetti, Maura
AU  - Xiang, Xianyuan
AU  - Shi, Yuan
AU  - Parhizkar, Samira
AU  - Grosch, Maximilian
AU  - Wind-Mark, Karin
AU  - Kunte, Sebastian T
AU  - Beyer, Leonie
AU  - Klaus, Carolin
AU  - Brösamle, Desirée
AU  - Wendeln, Ann-Christin
AU  - Osei-Sarpong, Collins
AU  - Heindl, Steffanie
AU  - Liesz, Arthur
AU  - Stoecklein, Sophia
AU  - Biechele, Gloria
AU  - Finze, Anika
AU  - Eckenweber, Florian
AU  - Lindner, Simon
AU  - Rominger, Axel
AU  - Bartenstein, Peter
AU  - Willem, Michael
AU  - Tahirovic, Sabina
AU  - Herms, Jochen
AU  - Buerger, Katharina
AU  - Simons, Mikael
AU  - Haass, Christian
AU  - Rupprecht, Rainer
AU  - Riemenschneider, Markus J
AU  - Albert, Nathalie L
AU  - Beyer, Marc
AU  - Neher, Jonas J
AU  - Paeger, Lars
AU  - Levin, Johannes
AU  - Höglinger, Günter U
AU  - Perneczky, Robert
AU  - Ziegler, Sibylle I
AU  - Brendel, Matthias
TI  - Regional desynchronization of microglial activity is associated with cognitive decline in Alzheimer's disease.
JO  - Molecular neurodegeneration
VL  - 19
IS  - 1
SN  - 1750-1326
CY  - London
PB  - Biomed Central
M1  - DZNE-2024-01115
SP  - 64
PY  - 2024
AB  - 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.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.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.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.
KW  - Animals
KW  - Microglia: metabolism
KW  - Alzheimer Disease: metabolism
KW  - Alzheimer Disease: pathology
KW  - Mice
KW  - Cognitive Dysfunction: metabolism
KW  - Humans
KW  - Brain: metabolism
KW  - Brain: pathology
KW  - Disease Models, Animal
KW  - Positron-Emission Tomography
KW  - Receptors, GABA: metabolism
KW  - Male
KW  - Mice, Transgenic
KW  - Connectome: methods
KW  - Female
KW  - Alzheimer’s disease (Other)
KW  - Brain connectivity (Other)
KW  - Dementia (Other)
KW  - Microglia (Other)
KW  - Microglia desynchronization (Other)
KW  - Microglia synchronicity (Other)
KW  - Neuroinflammation (Other)
KW  - PET (Other)
KW  - TSPO (Other)
KW  - Receptors, GABA (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C2  - pmc:PMC11375924
C6  - pmid:39238030
DO  - DOI:10.1186/s13024-024-00752-6
UR  - https://pub.dzne.de/record/271973
ER  -