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Published on: December 26, 2016
Microglia produce the amyloidogenic ABri peptide in familial British dementia
Abstract:
Mutations in ITM2B cause familial British, Danish, Chinese and Korean dementias. In familial British dementia (FBD) a mutation in the stop codon of the ITM2B gene (also known as BRI2 ) causes a C-terminal cleavage fragment of the ITM2B/BRI2 protein to be extended by 11 amino acids. This fragment, termed amyloid-Bri (ABri), is highly insoluble and forms extracellular plaques in the brain. ABri plaques are accompanied by tau pathology, neuronal cell death and progressive dementia, with striking parallels to the aetiology and pathogenesis of Alzheimer's disease. The molecular mechanisms underpinning FBD are ill-defined. Using patient-derived induced pluripotent stem cells, we show that expression of ITM2B/BRI2 is 34-fold higher in microglia than neurons, and 15-fold higher in microglia compared with astrocytes. This cell-specific enrichment is supported by expression data from both mouse and human brain tissue. ITM2B/BRI2 protein levels are higher in iPSC-microglia compared with neurons and astrocytes. Consequently, the ABri peptide was detected in patient iPSC-derived microglial lysates and conditioned media but was undetectable in patient-derived neurons and control microglia. Pathological examination of post-mortem tissue support ABri expression in microglia that are in proximity to pre-amyloid deposits. Finally, gene co-expression analysis supports a role for ITM2B/BRI2 in disease-associated microglial responses. These data demonstrate that microglia are the major contributors to the production of amyloid forming peptides in FBD, potentially acting as instigators of neurodegeneration. Additionally, these data also suggest ITM2B/BRI2 may be part of a microglial response to disease, motivating further investigations of its role in microglial activation. This has implications for our understanding of the role of microglia and the innate immune response in the pathogenesis of FBD and other neurodegenerative dementias including Alzheimer's disease.
Insights
Microglia, not neurons, produce amyloid-forming peptides in familial British dementia (FBD). This suggests these immune cells may initiate neurodegeneration and play a role in FBD and Alzheimer's disease pathogenesis.
Area of Science:
- Neuroscience
- Genetics
- Immunology
Background:
- Mutations in the ITM2B gene cause familial British dementia (FBD), characterized by amyloid-Bri (ABri) plaques and neurodegeneration.
- The precise molecular mechanisms and cellular sources of ABri peptide in FBD pathogenesis remain unclear.
- FBD shares pathological hallmarks with Alzheimer's disease, highlighting the need to understand its underlying mechanisms.
Approach:
- Utilized patient-derived induced pluripotent stem cells (iPSCs) to investigate ITM2B/BRI2 expression and ABri peptide production across different brain cell types.
- Analyzed gene expression data from human and mouse brain tissue to confirm cell-specific expression patterns.
- Examined post-mortem brain tissue and performed gene co-expression analysis to link ITM2B/BRI2 to microglial responses.
Key Points:
- ITM2B/BRI2 expression is significantly enriched in microglia compared to neurons and astrocytes.
- The amyloid-forming ABri peptide was detected in iPSC-derived microglia from FBD patients but not in neurons.
- Post-mortem tissues show ABri in microglia near amyloid deposits, and gene co-expression analysis implicates ITM2B/BRI2 in microglial responses.
Conclusions:
- Microglia are the primary producers of amyloid-forming peptides in familial British dementia.
- Microglia may act as instigators of neurodegeneration in FBD, contributing to disease pathogenesis.
- ITM2B/BRI2's role in microglial activation suggests potential involvement in innate immune responses in neurodegenerative diseases like FBD and Alzheimer's.
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