Aging and the Microglia Immune Response to Amyloid-β Peptide in the Primate Brain

Changiz Geula, Ph.D. and Joseph El Khoury, M.D.

Northwestern University Medical School

Funded in September, 2007: $200000 for 3 years


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Immune Cells in the Brain May Play a Pivotal Role in Alzheimer’s Disease

This study will determine the effects of age-related changes in human immune miocroglial cells in contributing to brain degeneration in Alzheimer’s disease.  

Alzheimer’s disease is characterized by the build-up of amyloid (a protein) in spaces between neurons termed plaques and also within neurons. The investigators’ prior animal studies have provided evidence that immune microglial cells, which reside in the brain, take up and clear out amyloid in mice; interference with this process results in accumulation of amyloid and premature death. Moreover, animal studies demonstrated that amyloid activates the immune microglial cells to release chemicals that produce inflammation around the plaque. The chemicals are toxic to neurons, however, and may result in their death. The investigators have found that amyloid is toxic to neurons when injected into brains of monkeys and that interference with microglia function reduces amyloid toxicity. Moreover, they observed that microglia from old human brains are deficient in taking up amyloid when compared with microglia from young brains.

The researchers hypothesize, therefore, that Alzheimer’s disease is produced by an age-related decrease in amyloid uptake by microglia, resulting in increased amyloid accumulation, which stimulates long-term release by immune microglial cells of toxic inflammatory substances (called “cytokines,” “chemokines,” and “reactive oxygen species”) and that this inflammation around plaques destroys brain cells.  They will test this hypothesis by studying brain tissue obtained from autopsies of ten young, ten middle-aged, and ten older people. They will isolate microglia from the brain tissues, expose it to fluorescence-labeled amyloid, and compare young and old, to determine whether: 1) microglia from older people are less effective in clearing amyloid; 2) microglial release of toxic chemicals is transient in young people but long-term in older people; 3) the long-term release of the toxic chemicals kills brain cells; and 4) compounds that inhibit chemical release reduce the damaging effects to nerve cells. 

Significance: If the results confirm that the role of microglial cells changes with age and leads to amyloid build-up and deadly inflammation, the findings may lead to development of new therapies for treating or preventing Alzheimer’s disease.


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Aging and the Microglia Immune Response to Amyloid-β Peptide in the Primate Brain

The brains of patients who suffer from Alzheimer’s disease (AD) present with a significant immune response in the form of a pronounced inflammatory reaction. The mediators of this response are microglia, the immune cells (macrophages) of the central nervous system. A large body of evidence indicates that this immune reaction is a response to deposition of the fibrillar form of the amyloid-β peptide (fAβ), which is increased in Alzheimer’s brains and accumulates in plaques. Exposure to fAβ transforms quiescent microglia to the activated state and results in significant microglial recruitment to the site of fAβ deposition. We have demonstrated that the aged primate brain is selectively vulnerable to the toxic effects of fAβ. Injection of plaque-equivalent concentrations of fAβ (200 pg) into the cerebral cortex of the aged rhesus monkey produced significant neuronal loss and importantly, resulted in microglial recruitment and activation. The toxicity of Aβ was age-dependent, as injections of the same concentration of fAβ produced no neuronal loss or microglia activation in young rhesus monkeys. This effect was also species-dependent. Similar injections in the aged rat were without effect.

Microglia phagocytose fAβ following binding of the peptide to class A scavenger receptors (SR-A). Collaborative studies of the investigators established that exposure of quiescent murine microglia to fAβ in vitro also initiates a signaling cascade, involving the CD36 scavenger receptor (scavenger receptor 2B), which results in production of reactive oxygen species (ROS), chemokines, and potentially cytotoxic cytokines. Our preliminary observations indicate that activation of microglia is indeed responsible, at least in part, for fAβ toxicity in the aged rhesus brain. Treatment of aged rhesus with macrophage inhibitory factor resulted in a significant reduction in the number of activated microglia and in the size of the area of damage in fAβ injection sites.

Our observation that fAβ  toxicity and microglia activation are seen in old but not young rhesus cortex combined with our finding that inhibition of microglia activation protects aged rhesus cortex against fAβ toxicity suggests that alterations in microglia function make a major contribution to fAβ toxicity in the aged primate and that microglia in the young primate cortex display a considerably different response to fAβ and hence little toxicity is seen in young primates. The proposed experiments will investigate age-related changes in the response to Aβ of microglia isolated from the human cortex. Given the recent evidence suggesting deleterious effects of the soluble oligomeric and protofibrillar Aβ, we shall also determine the effects of these conformations of Aβ on microglia.

Our recent preliminary evidence indicates that microglia from aged human brains display considerably reduced phagocytosis of Aβ when compared with microglia from young human brains. Aged microglia also displayed significantly reduced production of ROS in response to Aβ when compared with young microglia.

Based on the above observations, we hypothesize that microglia isolated from the aged human cerebral cortex will display significantly reduced phagocytosis of various conformations of Aβ when compared with microglia isolated from young brains. This is likely to give rise to greater accumulation of Aβ extracellularly, with the resultant chronic stimulation of CD36 receptor, activation of microglia and long term production of chemokines, cytokines, and ROS, causing neuronal degeneration. On the other hand, young microglia, despite the greater ability for production of ROS, efficiently phagocytose Aβ, likely reducing its extracellular levels, resulting in reduced stimulation of CD36, and only transient production of ROS, chemokines and cytokines.


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Changiz Geula, Ph.D. and Joseph El Khoury, M.D.

Changiz Geula, Ph.D., is Professor of Neuroscience at the Cognitive Neurology and Alzheimer’s Disease Center, Northwestern University, Feinberg School of Medicine, Chicago, IL. He assumed this position in November of 2007 following a 20 year tenure at Harvard Medical School, Boston, Massachusetts. Dr. Geula is the Director of the Laboratory for Cognitive and Molecular Morphometry at Northwestern University Medical School. He received his doctorate in Biopsychology/Neuroscience from Wayne State University, Detroit, Michigan. Postdoctoral training includes a fellowship in Neurochemistry at the University of Kentucky Medical School, Department of Neurology and Sanders-Brown Research Center on Aging, Lexington, Kentucky. He also completed a research fellowship in Neuroanatomy and Neuropathology at Harvard Medical School, Department of Neurology, Beth Israel Hospital.

Dr. Geula’s research interests have focused on the aging of the brain and neurodegenerative disorders that afflict the elderly, particularly Alzheimer’s disease. One line of research pursued in his laboratory concentrates on age-related changes in the nervous system, including changes in amyloid levels and microglia function, which contribute to selective neuronal loss and dysfunction in Alzheimer’s disease.