Francesca Tomasi received her B.A. from the University of Chicago and is now a microbiologist.
In 2009, researchers at UC Davis published a study reporting an unlikely connection between two very different things: amyloid plaques and bacterial biofilms. Amyloid plaques are a hallmark of Alzheimer’s disease. They are sticky buildups found over neurons that are caused by proteins that no longer fold properly. Biofilms, on the other hand, are slimy conglomerates of microbes that often stick to surfaces thanks to polymers produced by the participant bacteria. Biofilms have been implicated in increased bacterial pathogenicity such as in infections associated with contaminated medical devices – slimy bacterial communities are a lot harder to kill than individual microbes. Non-pathogenic bacteria also form biofilms, such as certain gut bacteria, in order to stick to host tissue and form colonies that help us digest food.
The specific connection researchers found at UC Davis nearly seven years ago is that amyloid plaques and bacterial biofilms actually look very similar in our immune systems’ eyes. Andreas Bäumler and colleagues showed this first by using mice models and then by using human cells. They injected mice with E. coli and salmonella and identified that curli fibrils, coiled fiber-like structures made by these bacteria, triggered the mice’s immune responses against these bugs. When they knocked out the microbes’ ability to aggregate, the same immune response was no longer triggered. Curli fibrils help bacteria adhere to host tissue and to each other in order to form biofilms.
Curli fibrils do in fact look just like amyloid fibers. And when Bäumler’s group presented human cells with both types of fibers, they observed identical immune responses, a finding that implicates morphological specificity rather than protein sequence specificity in inflammation. That is, the structures of these protein aggregates – both neuronal and bacterial – look the same to our immune systems and are thus treated the same way. Both trigger a type of immune response known as inflammation. When we have an infection, this response fights the infection and (hopefully) clears it. And when people get Alzheimer’s, doctors see a characteristic chronic inflammation in the brain that damages their neurons.
In mice, the immune response to curli fibrils is mediated by a protein called Toll-like receptor 2, abbreviated TLR-2. This protein is found on some cell surfaces and recognizes foreign material such as pathogens. When this happens, TLR-2 signals the immune system. Bäumler and colleagues used human immune cells called macrophages to test whether synthetic curli fibril proteins and amyloid plaque-causing proteins would trigger TLR-2 in vitro (in a lab setting). The group found that TLR-2 was triggered by both of these proteins, but only when they were allowed to aggregate.
Through the twentieth and beginning of the twenty-first centuries, scientists tried to figure out what was causing chronic inflammation in Alzheimer’s patients. When microbiology met neuroscience, a possible cause was finally identified. Curli fibrils and amyloid plaques are genetically two completely different things, but they seem to form nearly identical aggregate structures. Thus, some feature of these structures triggers the same innate immune response to elicit inflammation in affected parts of the body.
These findings have been key in the search for amyloid-related disease treatments (such as Alzheimer’s, Huntington’s, type 2 diabetes, and mad cow disease). If scientists can inhibit TLR-2-dependent cascades, the progression of these devastating illnesses could potentially be slowed, if not halted. We are still some ways away from completely understanding Alzheimer’s and related diseases, and we need a full picture of the disease and its specific causes before marketing treatments. Furthermore, potential implications of inhibiting TLR-2 responses (a form of immunosuppression) will need to be investigated before approaching this type of treatment method.
Despite the UC Davis and related studies almost a decade ago, additional potential connections between microbes and Alzheimer's disease remained under-studied and under the radar until recently. Earlier this month, however, a team of scientists and clinicians from around the world co-authored an editorial in the Journal of Alzheimer's Disease. Their article stresses the need for further research on specific microbes and their potential roles in Alzheimer's disease. The group draws from multiple published studies that have implicated microbes in the brain disorder.
The editorial points a finger at three microorganisms: the cold sore-causing Herpes Simplex 1 virus (HSV1), Chlamydia pneumonia bacteria, and various spirochete bacteria such as syphilis, all of which are reportedly present in the brains of many elderly people. For instance, they cite studies that have noted amplification of HSV1 DNA in the brains of immunosuppressed individuals. Furthermore, they write that pathogen hallmarks (such as microbial DNA) tend to co-localize with amyloid plaques in Alzheimer’s patients. Correlations have been deduced between testing positive for HSV1 infection and developing Alzheimer’s disease. More recently, Alzheimer’s has been shown to have a “communicable” feature – features of Alzheimer’s pathology have been found to be transmissible by inoculation of Alzheimer’s-afflicted cells to animal models. Similarities between syphilitic dementia (dementia caused by the bacteria that cause syphilis) and Alzheimer’s disease further underscore a potential connection, and some antivirals such as the drug acyclovir have been shown in vitro to block HSV1-induced amyloid pathology.
The editorial has received mixed reactions. Many have called the referenced studies insufficient; and while there might be a relationship between microbes and Alzheimer’s disease, causation and correlation have not been distinguished. For example, while it is known that many viruses and bacteria tend to be more prevalent in Alzheimer’s afflicted brains compared to healthy brains, this could be a consequence of the disease rather than a cause. Furthermore, what about all the evidence that some types of Alzheimer’s are hereditary? There are, after all, specific genes that have been implicated with increased risk of developing the disease. And while we know that certain aspects of our microbiomes are inherited during birth from our mothers, infection with HSV1, chlamydia, or syphilis is not hereditary.
In 1981, Barry Marshall proved that the bacterium Helicobacter pylori can cause stomach ulcers. Throughout the 1950s and 1960s, studies showed that some viruses can cause cancer (these are now known as oncoviruses). Whether or not the Microbe-Alzheimer’s hypothesis will join these pivotal medical discoveries will be determined if relevant studies end up being funded and undertaken.