Deadly Australian soil bacterium sheds light on infection hypothesis for Alzheimer’s disease.

Burkholderia pseudomallei www.npr.org

Researchers at Griffith University in Queensland, Australia, are the first to completely document the entire route by which bacteria can get into the brain by passing through the nasal mucosa, traveling up the trigeminal nerve, and entering the brain through the brainstem. James St. John and his colleagues infected mice with the soil bacterium Burkholderia pseudomallei, common in northern Australia and throughout South East Asia. Once sniffed up from rural dust the bacterium can travel to the brain in under 24 hours. The ensuing infection – melioidosis – is related to the disease glanders in horses and cattle and can lie dormant for up to 60 years, but if it erupts it is fatal in up to 50% of cases. These researchers believe the “royal road” they have discovered into the CNS may be shared by other bacteria like Staphylococcus and acne bacterium as well as by Chlamydia, which has been strongly implicated as a causative agent in Alzheimer’s disease.

Back in April, in a post titled “A new role for an old villain“, I reported the research of Rob Moir at Harvard University who has discovered that the traditional prime culprit in Alzheimer’s disease – the protein beta-amyloid – far from simply being a toxic neuron-killer actually has an evolved potent anti-bacterial function in the brain. Moir showed that beta-amyloid is highly effective against a wide spectrum of pathogens including Candida albicans, E. coli, Listeria, Enterococcus and Streptococcus. The corollary is that the brain must be capable of being exposed to bacterial and viral infections for such a molecule to be pressed into its protective role by evolution. Although no research group, until now, has reliably demonstrated the entire process by which a pathogen can be picked up from the environment and transported into different parts of the brain, many researchers have been furnishing us with parts of the picture – circumstantial evidence – and providing us with an alternative, some would say heretical, theory for what kicks off Alzheimer’s disease in the first place.

Brian Balin, in the US, has been investigating Chlamydia pneumoniae and has shown its presence in nerve pathways leading away from the olfactory mucosa and in the olfactory bulb of the brain. He has also documented its presence in other parts of the brain through electron microscopy and the identification of lipopolysaccharide proxy molecules. Angela Kamer has discovered the spirochaete Treponema (a major cause of periodontal disease) in the trigeminal nerve ganglion and in the majority of the Alzheimer’s disease post-mortem brains she has studied, and Ruth Itzhaki has accumulated evidence that herpes simplex virus can retreat from a cold sore on the lips, to the trigeminal nerve ganglion, which has connections to the brainstem and nearby temporal cortex.

Here is where James St. John enters the picture. Following bacterial inoculation into the noses of his experimental mice he noticed changes in the olfactory lining, which became rucked up or crenellated. He found Burkholderia amid the crenellations and in the underlying layer, the lamina propria, which is served by branches of the trigeminal nerve. Using a technique known as whole-mount immunohistochemistry he discovered patches of Burkholderia all along the trigeminal nerve, as its branches coalesced into the trigeminal ganglion. This ganglion lies inside the dura mater, the tough fibrous sheet that surrounds the brain, and projects into the brainstem. From sagittal sections of the heads of the mice they were able to track the bacterium over the entire trajectory of the trigeminal nerve from nose to brainstem. Assays from tissues surrounding the nerve proved negative for Burkholderia, demonstrating that it was specifically restricted to the nerve, and the use of a non-encapsulated form of the bacterium which cannot survive in the blood – only in nerve – again underlined the route taken. Once in the brainstem the bacterium spread further into the brain and down the spinal cord.

St. John and his collaborators believe they have established a common pathway that can be shared by any number of brain pathogens and this research will no doubt add impetus to those researchers, like Brian Balin, who are convinced that pathogens can cause Alzheimer’s disease.