In a study published in Neurobiology of Aging, Stanford radiologists Mike Zeineh, MD, PhD, and Brian Rutt, PhD, and their colleagues used a ultra-powerful magnetic-resonance-imaging (MRI) system to closely scrutinize postmortem tissue from the brains of people with and without Alzheimer’s disease. In four out of five of the Alzheimer's brains they looked at, but in none of the five non-Alzheimer's brains, they found what appear to be iron-containing microglia - specialized scavenger cells in the brain that can sometimes become inflammatory - in a particular part of the hippocampus, a key brain structure that's absolutely crucial to memory formation as well as spatial orientation and navigation.
Zeineh and Rutt told me they don’t know how the iron gets into brain tissue, or why it accumulates where it does. But iron, which in certain chemical forms can be highly reactive and inflammation-inducing, is ubiquitous throughout the body. Every red blood cell that courses through our microvasculature is filled with it. So one possibility - not yet demonstrated - is that iron deposits in the hippocampus could result from micro-injury to small cerebral blood vessels there.
As surprising as the iron-laden, inflamed microglia Zeineh, Rutt and their associates saw in Alzheimer's but not normal brains was what they didn't see. Surprisingly, in the brain region of interest there was no consistent overlap of either iron or microglia with the notorious amyloid plaques that have been long held by many neuroscientists and pharmaceutical companies to be the main cause of the disorder. These plaques are extracellular aggregations of a small protein called beta-amyloid that are prominent in Alheimer's patients’ brains, as well as in mouse models of the disease.
Because they weren't able to visualize small, soluble beta-amyloid clusters (now believed to to be the truly toxic form of the protein), Rutt and Zeineh don't rule out a major role for beta-amyloid in the early developmental stages of pathology in Alzheimer's.
But the early involvement of microglia in the disorder is becoming increasingly evident as Alzheimer's comes to be viewed as a product of neuroinflammation.
From our news release on this study:
[G]roups led by Stanford researchers such as neurologists Katrin Andreasson, MD, and Tony Wyss-Coray, PhD, and neurobiologist Ben Barres, MD, PhD, have previously fingered microglia as potential suspects in the early inflammatory pathology of the disease. This study, which adds the new finding that inflamed, iron-associated microglia are present in the hippocampus in Alzheimer’s, could advance the scientific community’s understanding of the disease.
“Microglia are the brain’s immune cells,” Zeineh told me when I interviewed him for the release:
In their resting state, they’re like police officers in the doughnut shop, sitting down and relaxing, their guns holstered, but keeping their eyes open while placidly munching on whatever cellular debris or stray substances might come their way. If they encounter anything suspicious, though, they whirl into action. Activated microglia are like officers with their guns out and firing, Zeineh said.
It seems, maybe, that iron doesn't go down so well with coffee and doughnuts.
Previously: Some headway on chronic fatigue syndrome: Brain abnormalities pinpointed, Blocking a receptor on brain's immune cells counters Alzheimer's in mice, When brain's trash collectors fall down on the job, neurodegeneration risk picks up and Neuroinflammation, microglia, and brain health in the balance
Photo by Duff Axsom