The role of iron in Alzheimer's disease

Iron-induced brain inflammation may be implicated in Alzheimer’s disease

Michael Zeineh, Ph.D., M.D.

Stanford University School of Medicine

Funded in September, 2015: $200000 for 3 years
LAY SUMMARY . ABSTRACT . BIOGRAPHY .

LAY SUMMARY

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Iron-induced brain inflammation may be implicated in Alzheimer’s disease

Might inflammation arising from iron that is converted into an active state in the brain be the third leg of the Alzheimer’s disease (AD) stool, joining the abnormal proteins “amyloid” and “tau” as the hallmarks of AD? Stanford investigators will use a combination of imaging techniques in preliminary steps to answering this question.

AD is characterized by abnormal accumulations of the protein called “amyloid” that builds up in spaces between brain cells, and by tangles within brain cells that consist of an abnormal form of the protein called “tau.” Together, these protein abnormalities eventually block brain cell communication. Cells degenerate and die. What has been elusive is exactly how cells and their communication connections (synapses) are destroyed. Increasingly, research has focused on the role in the brain that inflammation may play. Studies show that the amyloid protein can convert inactive iron in the brain into an active free-radical form that drives brain inflammation. Additionally, immune system microglial cells are located in areas of brain cell degeneration, especially in the “perforant” pathway that connects the whole brain with the  hippocampus, which is involved in cognition including memory. This pathway’s degeneration is thought to be the earliest stage of AD, related to the loss of the memory that typically occurs in early AD. 

Building on these findings, the Stanford radiologists imaged autopsied hippocampal tissue. They compared tissue from those who had AD prior to death to tissue from those who had not. They found activated iron in microglial cells only in the tissue samples from those with AD. This finding has led the Stanford investigators to hypothesize that inflammation that is associated with iron-laden microglial cells produces destruction of brain cells in AD, in synergy with amyloid and tau; and, that this degenerative process can be visualized using powerful 7T-MRI imaging.  
They will test this hypothesis in autopsied AD brain tissue. First, they will quantify the amount of inflammation-inducing iron versus inactive iron in the hippocampus, using 7T-MRI microscopy combined with electron microscopy. They anticipate that about 50 percent of the iron will be in the activated state, supporting an inflammatory role for iron. Second, they will determine whether iron-containing microglial cells are located in the performant pathway (the earliest site of neurodegeneration in AD) using both MRI and a technique called CLARITY that shows proteins (such as amyloid and tau). They anticipate that in AD tissues, compared to unaffected tissues, there will be fewer nerve fibers in the perforant pathway and a greater concentration of iron, suggesting iron as a causal factor in neuron destruction. Thereafter, they will translate this tissue imaging methodology into 7T-MRI scanners that can be used to scan patients. 

    Significance: If these brain tissue MRI imaging techniques indicate that iron has a major role in triggering AD degeneration and if these techniques can be translated into human imaging, this research will take science a step closer to determining how AD neurodegeneration occurs.     

ABSTRACT

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More than 5 million Americans suffer from AD, incurring an annual cost of approximately $200 billion. AD has typically been characterized as pathological accumulations of amyloid and neurofibrillary tangles. However, the mechanism of synaptic and neuronal destruction is unknown and novel therapies are needed. A growing field of investigation focuses on the role of neuroinflammation and microglia, the inflammatory cells of the brain. Recent work demonstrates that amyloid in vitro can convert the quiescent storage form of iron (Fe3+) to the free-radical producing form of iron (Fe2+). Microglia, in concert with pathological forms of iron accumulation, may play a pivotal role in neuronal degeneration in AD. Our work begins to fill in the picture of iron and inflammation in AD. Using specimen MRI and coregistered histology, we identified a pathological accumulation of iron-rich microglia in the hippocampal formation in AD, and this paper by and in the lab of the PI of this proposal is in press in Neurobiology of Aging. However, we still need to understand the interaction between iron and inflammation: specifically, we need to determine if iron is in an inflammatory state (i.e. ferrous (Fe2+) iron rather than ferric (Fe3+) iron). Furthermore, we need see if these iron-containing microglia are related to degradation of the main connection between the hippocampal formation and the remainder of the brain, the perforant pathway. Degeneration of this pathway is known to occur early in AD and is associated with impaired mnemonic function. Finally, we need to translate ex vivo imaging to in vivo application. In this proposal, we will: 1. Measure the valency state of iron (Fe2+ vs. Fe3+) that is identified by MRI in AD specimens 2. Determine the colocalization of iron-containing microglia and degradation of the perforant pathway by coregistering with specimen MRI with microscopy scans of specimens, and 3. Translate the ex vivo imaging paradigm to be ready for in vivo use by adapting the specimen MRI acquisition on a human 7.0T magnet with a human-compatible imaging timeframe. Deciphering the inflammatory nature of iron and its consequences on hippocampal circuitry would be instrumental in improving our understanding of the mechanism of neurodegeneration in AD and pave the way for using iron as a biomarker of inflammatory pathology.

KEYWORDS


Anatomy: Amyloid
Central nervous system
Hippocampus
Neuroanatomy
Conditions: Alzheimer's disease
Function: Memory
Technology: MRI
Neuroimmunology