Iron loading is a prominent feature of activated microglia in Alzheimer\u2019s disease patients

Boyd Kenkhuis,Antonios Somarakis,Boudewijn P F Lelieveldt,Jouke Dijkstra,Thomas Höllt,Lorraine De Haan,Oleh Dzyubachyk,Louise Van Der Weerd,Willeke M C Van Roon-Mom,Marieke E Ijsselsteijn,Noel F C C De Miranda

doi:10.1186/s40478-021-01126-5

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.

Highlights

Alzheimer’s disease is the most common cause of dementia, and is defined by the presence of amyloid-β (Aβ) plaques and tau tangles
Tissue acquisition Brain autopsy tissue of the middle temporal gyrus (MTG) of 12 Alzheimer patients and 9 age-matched controls was collected at the Leiden University Medical Center (LUMC), Netherlands Brain Bank (NBB) and the Normal Aging Brain collection Amsterdam (NABCA)
Iron-positive cells showed characteristic microglia morphology with a small soma and many thin processes (Fig. 1a) and quantification indicated a significant increase of ironpositive cells in Alzheimer patients compared to controls (P = 0.0024; Fig. 1b)

Summary

Introduction

Alzheimer’s disease is the most common cause of dementia, and is defined by the presence of amyloid-β (Aβ) plaques and tau tangles. A comparable yet disparate state coined the human Alzheimer microglia (HAM) has been identified [4] Upregulated genes in these subsets do indicate loss of homeostatic function and increased pro-inflammatory activation, and dysregulated iron-metabolism, manifested via upregulation of the FTL-gene and downregulation of FTH1 and SLC2A11 [4, 5]. FTL encodes the ferritin light chain (FTL) protein, the component of the major iron-storage complex ferritin, Kenkhuis et al acta neuropathol commun (2021) 9:27 responsible for the long term storage of iron. These transcriptomic findings coincide with previously observed ferritin+ microglia in Alzheimer’s disease [6, 7]. Though increased iron concentration likely plays a role, the exact link between the two has not yet been established

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