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Updated: Nov 17, 2025
Assessing Iron Deposition in the Brains of 5xFAD Mice by Perls'/DAB Staining
Published on: May 23, 2025
Iron loading is a prominent feature of activated microglia in Alzheimer's disease patients
Boyd Kenkhuis1,2, Antonios Somarakis3, Lorraine de Haan4
1Department of Human Genetics, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands. b.kenkhuis@lumc.nl.
Abstract:
Brain iron accumulation has been found to accelerate disease progression in amyloid-β(Aβ) positive Alzheimer patients, though the mechanism is still unknown. Microglia have been identified as key players in the disease pathogenesis, and are highly reactive cells responding to aberrations such as increased iron levels. Therefore, using histological methods, multispectral immunofluorescence and an automated in-house developed microglia segmentation and analysis pipeline, we studied the occurrence of iron-accumulating microglia and the effect on its activation state in human Alzheimer brains. We identified a subset of microglia with increased expression of the iron storage protein ferritin light chain (FTL), together with increased Iba1 expression, decreased TMEM119 and P2RY12 expression. This activated microglia subset represented iron-accumulating microglia and appeared morphologically dystrophic. Multispectral immunofluorescence allowed for spatial analysis of FTL+Iba1+-microglia, which were found to be the predominant Aβ-plaque infiltrating microglia. Finally, an increase of FTL+Iba1+-microglia was seen in patients with high Aβ load and Tau load. These findings suggest iron to be taken up by microglia and to influence the functional phenotype of these cells, especially in conjunction with Aβ.
Insights
Iron accumulation in microglia accelerates Alzheimer's disease progression. These iron-laden microglia infiltrate amyloid plaques and exhibit an activated, dystrophic phenotype, correlating with disease severity.
Area of Science:
- Neuroscience
- Neuropathology
- Immunology
Background:
- Brain iron accumulation is linked to accelerated Alzheimer's disease (AD) progression in amyloid-beta (Aβ) positive patients.
- Microglia, the brain's immune cells, are implicated in AD pathogenesis and respond to iron dysregulation.
Purpose of the Study:
- To investigate the presence and characteristics of iron-accumulating microglia in human Alzheimer's brains.
- To determine the effect of iron accumulation on microglial activation state and phenotype.
Main Methods:
- Histological methods and multispectral immunofluorescence were employed.
- An automated pipeline was developed for microglia segmentation and analysis.
- Expression of iron storage protein (ferritin light chain - FTL) and microglial markers (Iba1, TMEM119, P2RY12) were assessed.
Main Results:
- A subset of microglia with increased ferritin light chain (FTL) and Iba1 expression, alongside decreased TMEM119 and P2RY12, was identified.
- This subset, termed iron-accumulating microglia, displayed a dystrophic morphology and infiltrated Aβ plaques.
- Increased iron-accumulating microglia correlated with higher Aβ and Tau loads in Alzheimer's patients.
Conclusions:
- Microglia actively take up iron in the Alzheimer's brain.
- Iron accumulation influences microglial functional phenotype, particularly in the context of Aβ pathology.
- Iron-accumulating microglia represent a key cellular player in Alzheimer's disease progression.
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