About Diseases of Aging
Alzheimer’s Disease and Infection
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| Light micrograph of an amyloid plaque. (Image courtesy of Brian J. Balin, PhD.) |
For several years now investigators have recognized that inflammation plays a critical role in the development of Alzheimer’s disease. Some believe that inflammation comes from the deposition of amyloid itself, which forms into plaques in the brains of patients with Alzheimer’s disease. Although it is true that amyloid in plaques is inflammatory, it never has been explained satisfactorily why amyloid is deposited in senile plaques in the first place.
Pathology of Alzheimer’s Disease
Investigators at the Philadelphia College of Osteopathic Medicine (PCOM) being supported by FRIDA have provided evidence that amyloid processing is increased dramatically in infected cells in culture. They hypothesize that upon the death of infected glial cells in a patient’s brain several events will occur that contribute to the pathology of Alzheimer’s disease.
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| Light micrograph of a dystrophic neuron from a patient with Alzheimer’s disease. (Image courtesy of Brian J. Balin, PhD.) |
First, bacterial toxins, previously shown to be highly inflammatory, will be released into the environment around the nerve cell. Second, amyloid that has been overprocessed within the infected cell also will be released, beginning the process of plaque formation. Lastly, infectious bacterial elementary bodies are free to infect other cells in the localized area, beginning the process anew. In fact, this very scenario (not including the amyloid) has been proposed as the initial event in developing atherosclerosis.
The FRIDA-supported investigator’s hypothesis continues that the inflammatory cycle then will continue via the bacterial toxins and amyloid resulting in damage to neurons leading to the formation of tangles and, ultimately, to neuronal cell death.
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| Electron micrograph of cells infected with C. pneumoniae. (Image courtesy of Brian J. Balin, PhD.) |
What evidence indicates that this bacteria is infecting the brains of patients suffering from Alzheimer’s disease? Dr. Brian J. Balin and his collaborators, Drs. Denah Appelt and Jamie Arking, have been able to use electron microscopy to produce photographs that show what an active infection by C. pneumoniae looks like in a sample taken from a patient who died after suffering from Alzheimer’s disease.
Evidence supportive of their photographic data was found in 17 of 19 patients with Alzheimer’s disease. In age-matched controls, the bacteria was found in only 1 of 19 patient samples. Several components of the bacteria have been shown to be highly inflammatory. They include a compound called endotoxin and a family of proteins called heat shock proteins. Thus we now know that the bacteria is present in the brain of many patients with Alzheimer’s disease, and we know that the bacteria has the potential to be highly inflammatory. What is not clear is whether Alzheimer’s disease makes the brain susceptible to infection or whether infection makes the brain susceptible to Alzheimer’s disease. This will be determined by treating the bacteria and testing whether patients improve and through further basic research.
Cutaneous T-Cell Lymphoma and Infection
A protein found to be a stimulatory factor for malignant T cells from patients with cutaneous T-cell lymphoma (CTCL) recently has been shown to be a product of the bacteria C. pneumoniae. (Image courtesy of J. Todd Abrams, PhD.)
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| Expression of SAF on C. pneumoniae in cell culture. (Image courtesy of J. Todd Abrams, PhD.) |
Researchers, including the President of FRIDA, recently published findings demonstrating the intimate association of the CTCL-associated stimulatory factor, which they named Sezary T-cell activating factor (SAF), and the bacterium C. pneumoniae. This research, which took place over a decade, demonstrate that (1) SAF could stimulate malignant cells to grow in laboratory cultures; (2) SAF is observed on the surface of C. pneumoniae bacteria in infected cells (figure left); (3) evidence of C. pneumoniae infection is found in the majority of patients suffering from CTCL; and (4) signs of bacterial infection disappear when the lymphoma goes into remission after effective therapy with psoralen and ultraviolet A treatment.
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| Expression of SAF in samples taken before (A) and after (B) treatment. (Images courtesy of J. Todd Abrams, PhD.) | ||
What is so exciting about these findings is that it provides important clues about how lymphomas develop and how they might be prevented. Furthermore, they suggest that inflammation could play a role in converting healthy cells into dysfucntional ones that could eventually become cancerous.
How could infection by C. pneumoniae cause CTCL? The researchers speculate that transient infection of the skin by these bacteria may be common, but that chronic infections may occur in individuals who can not successfully inhibit bacterial replication. These investigators suggest that this chronic infection would stimulate the proliferation of T cells reactive with the bacteria. Over a long period of time such a chronic infection would result in the accumulation of T cells in the skin and involved areas would be observed in the form of patches and plaques. Because cells that continuously divide are more susceptible to the development of genetic errors, transformation can occur more readily in chronically stimulated T cell, leading to a more aggressive malignancy in some individuals. These investigators also suggest that chronic infection in the skin by other types of bacteria also could produce the same sort of effect, and that chronic infections reasonably could be associated with nonlymphoid cancers such as colorectal carcinoma and prostate cancer. Studies to examine this possibility are now being initiated in FRIDA-supported laboratories.
Rheumatoid Arthritis
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| The redundancy mechanism appears to depend on properties shared by CD44 and RHAMM molecules: ligand binding and support of cell trafficking. (Figure courtesy of David Naor, MD.) |
Rheumatoid arthritis is a disease of aging with a large inflammatory component. These characteristics led FRIDA to fund a project to investigate the migration of inflammatory cells into joints. Results provided new insights into a fascinating process of how protein complexes are arranged and could lead to a new target for treatment
Dr. David Naor and colleagues used the collagen-induced mouse arthritis model. They found that joint inflammation in collagen-induced arthritis is more aggravated in CD44-knockout mice than in control mice. They also found evidence of substitution of the CD44 protein by a protein called RHAMM (receptor for hyaluronan-mediated motility) was the cause of the exacerbation of the disease. RHAMM has similar biologic binding characteristics in that it too is a hyaluronan receptor and also supports cell migration. Interestingly, they suggest a mechanistic explanation for the redundancy that depends neither on an increase in the amount of the compensating protein (RHAMM) nor on structural similarity between the original CD44 molecule and RHAMM. The backup process is dependent, however, on two key properties shared by the two molecules: ligand binding and support of cell trafficking.