A human study identifies region specific iron-containing microglia in Alzheimer’s brains.


Examining post-mortem tissue from the brains of people with Alzheimer’s disease, Stanford University researchers state they have identified what appear to be iron-containing microglia, specialized scavenger cells that sometimes become inflammatory,  in a particular part of the hippocampus, a key brain structure whose integrity is critical to memory formation.  In post-mortem brain tissue from people not diagnosed with Alzheimer’s, neither the iron deposits nor the scavenger cells engulfing them were present in that brain region.  The team state that the findings suggest that high-field magnetic resonance imaging, in particular an advanced version called 7T MRI that uses a powerful 7-Tesla magnet, could someday be used to diagnose and monitor Alzheimer’s patients earlier than is currently possible.  The opensource study is published in the journal Neurobiology of Aging.

Previous studies show that a long-held hypothesis holds that the most notorious feature of Alzheimer’s disease, amyloid plaques, is the main cause of the disorder. These plaques are extracellular aggregations of a small protein called beta-amyloid that are prominent in diseased patients’ brains, as well as in mouse models of the disease. The other most cited key player is tau, another Alzheimer’s-associated protein that abnormally aggregates into threadlike tangles inside nerve cells. Surprisingly, in the brain region of interest there was no consistent overlap between the iron-laden microglia and the amyloid plaques or tau.

The current study shows that the bulk of microglia found in association with iron were in an activated, inflammatory state. Alzheimer’s is increasingly understood to involve brain inflammation with earlier studies from the group identifying microglia as potential suspects in the early inflammatory pathology of the disease. The new findings that inflamed, iron-associated microglia are present in the hippocampus in Alzheimer’s and are observable by 7T MRI, which could advance the scientific community’s understanding of the disease.

The researchers note that this was a preliminary study performed on a small number of human brain specimens, which are generally difficult to obtain.  However, previous imaging studies using mouse models of Alzheimer’s disease had revealed the presence in these mice’s brains of tiny, mysterious black dots that could signal the presence of iron, an element that shows up dark under MRI and, and in certain chemical forms can be highly reactive and inflammation-inducing. The team state that these mouse studies had raised the possibility that this iron might be tightly associated with amyloid plaques.

The current study validated these animal models by probing slabs of tissue taken from several places within the brains of each of five Alzheimer’s and five control brain specimens.  These slabs were scanned via 7T MRI, which can provide hair’s-thickness resolution in three dimensions. In images from four out of the five Alzheimer’s brains, and none of the control brains, the researchers observed black dots in the subiculum, a component of the hippocampus. Previous studies show that the hippocampus is known to incur some of the earliest and most severe ravages of Alzheimer’s disease.  The team then carefully sectioned the tissue slabs into several hundred ultrathin sections; incubated those sections with stains that pinpoint the location of iron, microglia, amyloid plaques and tau; and analyzed the resulting stain patterns.

The data findings showed that iron, frequently engulfed by microglia, was occupying the same spots in the subiculum of Alzheimer’s brains where 7T MRI had found black dots. Those microglia were mostly in an activated state.  As notable was the relative absence of amyloid plaques in these spots.  The researchers note that they didn’t consistently find the iron associated with plaques as was expected despite their best efforts.

The results show that amyloid is found all over the brain in Alzheimer’s disease, and often in the brains of people who’ve died with no complaints of memory loss at all.  Tau is also found throughout the Alzheimer’s brain. This iron-microglia complex, in contrast, really seems concentrated in the subiculum, and, so far, it’s showing up only in brains from Alzheimer’s patients.

The lab stress that, for now, they don’t fully understand how iron gets into brain tissue, or why it accumulates where it does. They hypothesize that micro-injury to the small cerebral blood vessels there was one possibility.  The researchers cautioned that the stains used in the current study wouldn’t have been able to visualize soluble clusters of beta-amyloid, now increasingly believed to be the protein’s toxic form, as opposed to the aggregated plaques. Soluble amyloid may yet be playing a major if still poorly understood role, they state.

The team now plan to explore these findings further by examining more wide-ranging areas of the brain and to stain for more cell types within larger numbers of post-mortem brain specimens. They also plan to hunt for iron-filled microglia in the brains of living patients during the early stages of neurodegeneration and memory loss that precede the onset of Alzheimer’s disease. They go on to conclude that their ultimate goal is to translate these imaging findings into clinical tools to help in the fight against dementia.

Source:  The Stanford University School of Medicine

Histologic triple staining for 3,3′-diaminobenzidine (DAB)-iron, CD163, and amyloid beta on 3 additional elderly controls demonstrates the absence of iron-containing microglia in the proximal subiculum. Images were windowed and color balanced to have similar contrast.  Activated iron-containing microglia in the human hippocampus identified by magnetic resonance imaging in Alzheimer disease.  Zeineh et al 2015.

Histologic triple staining for 3,3′-diaminobenzidine (DAB)-iron, CD163, and amyloid beta on 3 additional elderly controls demonstrates the absence of iron-containing microglia in the proximal subiculum. Images were windowed and color balanced to have similar contrast. Activated iron-containing microglia in the human hippocampus identified by magnetic resonance imaging in Alzheimer disease. Zeineh et al 2015.

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