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Microglial Heterogeneity and Its Potential Role in Driving Phenotypic Diversity of Alzheimer's Disease
Stefano Sorrentino1,2, Roberto Ascari3, Emanuela Maderna2
1CNR NANOTEC-Institute of Nanotechnology, 73100 Lecce, Italy.
Abstract:
Alzheimer's disease (AD) is increasingly recognized as a highly heterogeneous disorder occurring under distinct clinical and neuropathological phenotypes. Despite the molecular determinants of such variability not being well defined yet, microglial cells may play a key role in this process by releasing distinct pro- and/or anti-inflammatory cytokines, potentially affecting the expression of the disease. We carried out a neuropathological and biochemical analysis on a series of AD brain samples, gathering evidence about the heterogeneous involvement of microglia in AD. The neuropathological studies showed differences concerning morphology, density and distribution of microglial cells among AD brains. Biochemical investigations showed increased brain levels of IL-4, IL-6, IL-13, CCL17, MMP-7 and CXCL13 in AD in comparison with control subjects. The molecular profiling achieved by measuring the brain levels of 25 inflammatory factors known to be involved in neuroinflammation allowed a stratification of the AD patients in three distinct "neuroinflammatory clusters". These findings strengthen the relevance of neuroinflammation in AD pathogenesis suggesting, in particular, that the differential involvement of neuroinflammatory molecules released by microglial cells during the development of the disease may contribute to modulate the characteristics and the severity of the neuropathological changes, driving-at least in part-the AD phenotypic diversity.
Insights
Microglia heterogeneity in Alzheimer's disease (AD) influences disease presentation. Analyzing brain samples revealed distinct neuroinflammatory profiles, suggesting microglial roles in AD
Area of Science:
- Neuroscience
- Immunology
- Neuropathology
Background:
- Alzheimer's disease (AD) is a heterogeneous disorder with varying clinical and neuropathological phenotypes.
- The molecular basis for this variability is not fully understood, but microglial cells and their cytokine release are implicated.
- Microglia are key immune cells in the brain, potentially influencing AD progression through inflammatory responses.
Purpose of the Study:
- To investigate the heterogeneous involvement of microglia in Alzheimer's disease.
- To analyze neuropathological and biochemical differences in AD brain samples related to microglial activity.
- To identify potential molecular markers contributing to AD phenotypic diversity.
Main Methods:
- Neuropathological analysis of microglial morphology, density, and distribution in AD brain samples.
- Biochemical analysis of brain tissue to measure levels of specific inflammatory factors (cytokines, chemokines, MMPs).
- Molecular profiling of 25 inflammatory factors to stratify AD patients into neuroinflammatory clusters.
Main Results:
- Significant differences in microglial morphology, density, and distribution were observed among AD brains.
- Elevated brain levels of IL-4, IL-6, IL-13, CCL17, MMP-7, and CXCL13 were found in AD compared to controls.
- AD patients were stratified into three distinct neuroinflammatory clusters based on molecular profiling.
Conclusions:
- Neuroinflammation plays a critical role in Alzheimer's disease pathogenesis.
- Differential microglial involvement and the release of specific inflammatory molecules contribute to AD heterogeneity.
- Microglial-derived factors may modulate the severity and characteristics of neuropathological changes, driving AD phenotypic diversity.
