30 October 2002 17:00 EST

by Martina Habeck

Infecting normal mice intranasally with the respiratory pathogen Chlamydia pneumoniae promotes plaque development consistent with Alzheimer's disease, US researchers will report next month at the Society for Neuroscience meeting in Orlando. The finding provides the Alzheimer's world with a long-needed experimental model for sporadic, late-onset Alzheimer's disease (AD) - and, possibly, with a culprit for the disease.

Human AD can be attributed to a genetic defect in only 5% of cases. "The question in my mind has always been: How do you take a disease that is this prevalent and explain its presence in a genetically heterogeneous population such as human beings?" said Karl Herrup, professor of neurosciences at Case Western Reserve University.

Infection with C. pneumoniae is a possible answer. A cousin of the more widely known sexually-transmitted C. trachomatis, C. pneumoniae is a common respiratory pathogen that causes acute and chronic conditions such as pneumonia, sinusitis and chronic obstructive pulmonary disease. A small bacterium, it can survive inside host cells for years and cause inflammatory responses.

C. pneumoniae made the news in the early 1990s, when it was found living in atherosclerotic plaques. Since then, C. pneumoniae infection has been implicated in the development of atherosclerosis. Curious to see whether it can also infect the nervous system, Brian Balin, Denah Appelt (now at Philadelphia College of Osteopathic Medicine), and Alan Hudson of Wayne State University analyzed post-mortem brains of 38 AD patients and controls.

A majority of AD patients had the bacterium in brain regions affected by the disease, while only one control was PCR-positive. The researchers even succeeded in culturing the bacterium isolated from AD brains.

A few negative reports followed, but chlamydiologist James Mahony of McMaster University believes these were due to sampling errors, because cutting serial sections within a paraffin block is "hit and miss." There is "no question in my mind that [chlamydia] is in the brain," says Mahony, who has corroborated Balin's findings. But the question remains whether it plays a causal role in AD.

Four years on, Balin and Appelt presented new data that caught the attention of virtually every delegate at the International Alzheimer's meeting in Sweden in July this year. Scott Little, a post-doc in Appelt's and Balin's lab, had infected non-transgenic BALB/c mice with a strain of C. pneumoniae isolated from an AD patient or vehicle alone.

Within 1-3 months, the researchers found plaques immunoreactive for A-beta 1-42 in the mouse brains. According to Appelt, the plaque load in infected animals rose over time and did not clear a year after infection. Control animals did not develop comparable plaques.

Herrup, who attended the meeting in Sweden, said the study was "well done" and "rigorously analyzed," which demanded that Alzheimer's researchers take serious note.

For a start, someone else must confirm the results. Meanwhile, Balin and Appelt have already done their own control experiments, and have infected BALB/c mice with a respiratory strain of C. pneumoniae. Preliminary evidence indicates this strain also promotes plaque development in the BALB/c brain, they will report at the Society for Neuroscience meeting in Orlando this month.

The jury is still out as to whether the infected mice also develop the second pathogenic hallmark of AD, neurofibrillary tangles. Appelt and Balin are investigating this, and are also gearing up to do some behavioral studies.

"I think the most stunning implication is that the mouse nervous system is capable of producing Alzheimer-like plaques without the use of genetic trickery," said Herrup. Having a non-genetic model of AD would enhance the field and "make our drug- and therapy-testing much more apprehensive."

Mahony agrees: "It will be very interesting to play with the model and see if you can block the formation of plaques by intervening at some point in whatever pathway of events you think occurs." He suggests blocking the action of cytokines, to see whether chlamydia contributes to inflammation that may play a key role in AD.

Balin and Appelt have already found another clue to chlamydia's role in AD. Having infected cultured monocytes and endothelial cells with C. pneumoniae, they observed that it actually upregulates the production and processing of the amyloid protein. "We think that there is a direct effect of the organism on amyloid, and that is how we think it will play into the Alzheimer problem," Balin said.

Time and more research will tell whether and how C. pneumoniae is involved the development of AD. "My prediction would be that we are not looking at the cause of all AD," said Herrup, "but that we might actually be getting insight into the kinds of insults that lead to the development of the sporadic form. We already think that vascular factors predispose. To have another route to disease can only help the field."

Balin now wants to set up clinical trials testing the effect of antibiotics used against C. pneumoniae in patients with late-onset AD. "Right now, we are thinking that combining antibiotics and anti-inflammatory drugs might be instrumental in treating AD," he added. Antibiotics alone might offer hope to people with sporadic AD who show signs of chlamydia infections, he says, but it remains uncertain whether antibiotics can ever eradicate the organism permanently.

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