Related Experiment Video
Updated: Jun 7, 2025
Assessing Iron Deposition in the Brains of 5xFAD Mice by Perls'/DAB Staining
Published on: May 23, 2025
Detection of molecular markers of ferroptosis in human Alzheimer's disease brains
Emily Mayr1, Jonas Rotter1, Heidrun Kuhrt1
1Institute of Anatomy, Leipzig University, Leipzig, Germany.
Background:
We have previously shown that droplet degeneration (DD) signifies the beginning of neuritic plaque formation during Alzheimer's disease (AD) pathogenesis. As microglia associated with neuritic plaques exhibited strong ferritin expression and Perl's iron staining showed iron in microglia, droplet spheres and neuritic plaque cores, we hypothesized that DD is a form of ferroptosis.
Objective:
Detection of molecular markers of ferroptosis in AD brains.
Methods:
Immunohistochemical detection of transferrin receptor (TfR) and ferritin as ferroptosis markers in prefrontal cortex of AD brains, investigation of spatial correlation of these with histopathological hallmarks of AD, visualization of ferroptotic marker genes by in situ hybridization, comparison of expression of ferroptosis genes with snRNAseq analyses and comparison of TfR and ferritin expression in different neurofibrillary tangle (NFT) stages.
Results:
TfR was found on neurons that appeared to be degenerating and exhibited typical features of droplet degeneration. Co-localization with hyperphosphorylated tau (p-tau) was a rare event. TfR-positive neurons increased with higher NFT stages as did ferritin expression in microglia. mRNA of genes linked to ferroptosis was detected in pretangles and p-tau negative neurons, less in DD. snRNAseq analyses support a link between AD, ferroptosis and TfR as a ferroptosis marker.
Conclusions:
Increased expression of TfR and ferritin in high NFT stages, demonstration of ferroptotic marker genes in Alzheimer's lesions, as well as snRNAseq analyses strengthen our hypothesis that DD represents ferroptosis. Because of the morphological similarity between TfR-positive structures and DD, TfR might be an early ferroptosis marker expressed transiently during AD pathogenesis.
Insights
Droplet degeneration in Alzheimer's disease (AD) is a form of ferroptosis, indicated by increased transferrin receptor (TfR) and ferritin. TfR may be an early marker of this iron-dependent cell death in AD.
Area of Science:
- Neuroscience
- Pathology
- Cell Biology
Background:
- Droplet degeneration (DD) precedes neuritic plaque formation in Alzheimer's disease (AD).
- Microglia in AD show ferritin expression and iron deposition, suggesting a role for iron in pathogenesis.
- Previous findings indicated iron in microglia, droplet spheres, and neuritic plaque cores.
Purpose of the Study:
- To detect molecular markers of ferroptosis in Alzheimer's disease brains.
- To investigate the role of ferroptosis in Alzheimer's disease pathogenesis.
Main Methods:
- Immunohistochemical detection of transferrin receptor (TfR) and ferritin in AD prefrontal cortex.
- Assessing spatial correlation of TfR and ferritin with AD histopathological hallmarks.
- Visualizing ferroptotic marker genes using in situ hybridization.
- Comparing ferroptosis gene expression with snRNAseq data.
- Evaluating TfR and ferritin expression across different neurofibrillary tangle (NFT) stages.
Main Results:
- TfR was observed on degenerating neurons exhibiting DD features.
- TfR-positive neurons and microglial ferritin expression increased with higher NFT stages.
- mRNA of ferroptosis-related genes was detected in early AD lesions.
- snRNAseq analyses supported a link between AD, ferroptosis, and TfR.
Conclusions:
- DD in AD pathogenesis is likely a form of ferroptosis.
- Increased TfR and ferritin expression in advanced NFT stages supports this hypothesis.
- TfR may serve as an early, transient ferroptosis marker in Alzheimer's disease.
