The microglial translocator protein (TSPO) in Alzheimer's disease reflects a phagocytic phenotype

Area of Science:

• Neuroscience
• Immunology
• Pathology

Background:

• Translocator protein (TSPO) is a mitochondrial protein expressed by microglia, serving as a marker for neuroinflammation in Alzheimer's disease (AD) PET imaging.
• Previous studies indicated increasing TSPO load in the cerebral cortex with AD progression, correlating with PET scan findings.
• Understanding the microglial phenotype associated with TSPO is crucial for interpreting PET signals in AD patients.

Purpose of the Study:

• To characterize the microglial phenotype associated with Translocator protein (TSPO) expression in human Alzheimer's disease (AD).
• To aid the interpretation of TSPO-targeting positron emission tomography (PET) signals in patients.
• To investigate the cellular localization of TSPO in the human brain during AD progression.

Main Methods:

• Human post-mortem temporal lobe and cerebellum sections from individuals staged by Braak group were analyzed.
• Fluorescent double labeling was performed for TSPO and microglial markers (Iba1, HLA-DR, CD68, MSR-A, CD64).
• Image quantification using QuPath software and qualitative analysis with astrocyte (GFAP), endothelial cell (CD31), and perivascular macrophage (CD163) markers were conducted.

Main Results:

• CD68+TSPO+ double-labeled cells, indicating phagocytic microglia, were significantly higher than other microglial markers across Braak stages and brain regions.
• MSR-A+TSPO+ microglia were the second most abundant.
• TSPO was also found in endothelial cells but not in astrocytes or perivascular macrophages.

Conclusions:

• TSPO expression in the human AD brain is predominantly associated with a phagocytic microglial phenotype (CD68+).
• This finding suggests TSPO PET signal may reflect ongoing neurodegeneration and microglial phagocytic activity.
• The study provides crucial cellular context for interpreting TSPO-based PET imaging in Alzheimer's disease.