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Regional desynchronization of microglial activity is associated with cognitive decline in Alzheimer's disease
Artem Zatcepin1,2, Johannes Gnörich3,4, Boris-Stephan Rauchmann5,6
1Department of Nuclear Medicine, University Hospital, LMU Munich, Munich, Germany. Artem.Zatcepin@med.uni-muenchen.de.
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.
Insights
Microglial desynchronization, assessed via TSPO-PET imaging, shows promise as a biomarker for Alzheimer's disease (AD) progression and cognitive decline. This study reveals a potential "microglia connectome" linked to neurodegeneration.
Area of Science:
- Neuroscience
- Neuroimaging
- Biomarker Discovery
Background:
- Microglial activation is a key feature of Alzheimer's disease (AD) neuropathology.
- The regional interplay and synchronization of microglia in the brain remain poorly understood.
- This study investigates microglial desynchronization as a potential AD biomarker.
Purpose of the Study:
- To explore the existence of a "microglia connectome" and its alterations in AD.
- To investigate microglial desynchronization as a potential biomarker for AD progression.
- To correlate microglial desynchronization with cognitive performance in AD patients.
Main Methods:
- Microglia depletion in mice to assess 18 kDa translocator protein (TSPO)-PET interregional correlation coefficients (ICCs).
- Evaluation of dysfunctional microglia and AD pathophysiology on TSPO-PET ICCs in mouse models.
- Translation to a human AD-continuum dataset and correlation with cognitive performance.
- Single-cell radiotracing (scRadiotracing) in mice to confirm the microglial source of desynchronization.
Main Results:
- Microglia depletion led to significant reductions in TSPO-PET ICCs, confirming microglia-specific desynchronization.
- AD mouse models showed reduced microglial synchronicity, linked to increased radiotracer uptake variability.
- Human AD-continuum data revealed stage-dependent reductions in microglia synchronicity correlating with cognitive decline.
- scRadiotracing confirmed microglia as the source of the observed TSPO signal.
Conclusions:
- First evidence for assessing a microglia connectome in the mouse brain using TSPO-PET imaging and scRadiotracing.
- Microglial synchronicity is closely associated with cognitive decline in Alzheimer's disease.
- Microglial desynchronization may serve as an independent, personalized biomarker for AD progression.
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