Microglial Reactivity Correlates with Presynaptic Loss Independent of β-Amyloid and Tau
Guoyu Lan1,2, Xuhui Chen3, Jie Yang1
1Shenzhen Bay Laboratory, Institute of Biomedical Engineering, Shenzhen, China.
Objective:
Triggering receptor expressed on myeloid cells-2 (TREM2) and progranulin (PGRN) are critical regulators of microglia activation and can be detected in cerebrospinal fluid (CSF). However, whether microglial reactivity is detrimental or neuroprotective for Alzheimer disease (AD) is still debatable.
Methods:
We identified 663 participants with baseline β-amyloid (Aβ) positron emission tomography (PET) and CSF biomarker data, including phosphorylated tau181 (p-Tau181), soluble TREM2 (sTREM2), PGRN, and growth-associated protein-43 (GAP-43). Among them, 254 participants had concurrent longitudinal CSF biomarkers. We used multivariate regression analysis to study the associations of CSF microglial biomarkers with Aβ PET, CSF p-Tau181, and CSF GAP-43 cross-sectionally and longitudinally. A Chinese aging cohort's independent CSF samples (n = 65) were analyzed as a validation.
Results:
Higher baseline levels of CSF microglial biomarkers were related to faster rates of CSF sTREM2 increase and CSF PGRN decrease. Elevated CSF p-Tau181 was associated with higher levels of CSF microglial biomarkers and faster rates of CSF sTREM2 increase and CSF PGRN decrease. In both cohorts, higher Aβ burden was associated with attenuated CSF p-Tau181 effects on CSF microglial biomarker increases. Independent of Aβ PET and CSF p-Tau181 pathologies, higher levels of CSF sTREM2 but not CSF PGRN were related to elevated CSF GAP-43 levels and faster rates of CSF GAP-43 increase.
Interpretation:
These findings suggest that higher Aβ burden may attenuate the p-Tau-associated microglial responses, and TREM2-related microglial reactivity may independently correlate with GAP-43-related presynaptic loss. This study highlights the two-edged role of microglial reactivity in AD and other neurodegenerative diseases. ANN NEUROL 2024;95:917-928.
Insights
Microglial activation markers in cerebrospinal fluid (CSF) show complex roles in Alzheimer disease (AD). Higher amyloid burden may alter tau-associated microglial responses, with TREM2 signaling linked to presynaptic loss.
Area of Science:
- Neuroscience
- Immunology
- Biochemistry
Background:
- Microglia, the brain's immune cells, play a crucial role in neuroinflammation and are implicated in Alzheimer disease (AD) pathogenesis.
- Triggering receptor expressed on myeloid cells-2 (TREM2) and progranulin (PGRN) are key regulators of microglial function and can be measured in CSF.
- The precise role of microglial activation in AD—whether neuroprotective or detrimental—remains a subject of ongoing investigation.
Purpose of the Study:
- To investigate the associations between CSF levels of microglial biomarkers (sTREM2, PGRN) and core AD pathologies, including beta-amyloid (Aβ) burden, phosphorylated tau (p-Tau181), and synaptic dysfunction (GAP-43).
- To explore the dynamic changes in CSF microglial biomarkers over time and their relationship with AD biomarkers.
- To elucidate the independent contribution of TREM2 and PGRN pathways to neurodegeneration in AD.
Main Methods:
- Cross-sectional and longitudinal analysis of CSF biomarkers (sTREM2, PGRN, p-Tau181, GAP-43) and Aβ PET imaging in 663 participants.
- Multivariate regression models were employed to assess relationships between CSF microglial markers and AD pathologies.
- Validation was performed using an independent cohort of 65 aging individuals.
Main Results:
- Higher baseline CSF microglial biomarker levels correlated with faster increases in sTREM2 and decreases in PGRN over time.
- Elevated CSF p-Tau181 was linked to higher CSF microglial markers and accelerated changes in sTREM2 and PGRN.
- Increased Aβ burden attenuated the effect of p-Tau181 on microglial biomarker changes; elevated CSF sTREM2, but not PGRN, was independently associated with increased GAP-43 and synaptic dysfunction.
Conclusions:
- Amyloid pathology may modulate tau-associated microglial responses, suggesting a complex interplay in AD.
- TREM2-mediated microglial reactivity appears to be independently associated with synaptic damage, as indicated by GAP-43 levels.
- These findings underscore the dual role of microglial activation in AD and other neurodegenerative conditions, highlighting TREM2 and PGRN as potential therapeutic targets.
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