Alzheimer’s Disease (AD) affects around half a million people in the UK, though its impacts spread much wider, devastating the lives of families and friends of sufferers. It is a type of dementia, a group of diseases associated with memory loss, confusion, mood variations and difficulties in communicating. Knowledge about the causes of AD remains elusive, though its symptoms are thought to stem from deposits of naturally occurring proteins, tau and amyloid. These become malformed in AD, forming tau tangles, and beta-amyloid proteins that form plaques. Both tau tangles and beta-amyloid plaques result in the death of brain cells, disrupting the neuronal network, and so leading to cognitive impairment. Another cause of symptoms is the reduction in acetylcholine, which is a type neurotransmitter, the chemical signals that allow neurons to communicate.
Risk factors for AD include, old age, being female, having diabetes or heart disease, lack of exercise, genetic predispositions, and drinking excessive amounts of alcohol. Another risk factor is earning its place on this list – having gum disease. Evidence has been mounting of a link between developing AD and infection with Porphyromonas gingivalis, the bacterium that causes chronic periodontitis, commonly known as gum disease. The connection has found support in a paper published in Science Advances recently.
The paper found the bacterium and the toxic proteins they secrete, known as gingipains, in brain samples of deceased Alzheimer’s patients, as well as P. gingivalis DNA in the spinal fluid of living patients. These gingipains are cysteine proteases, a type of enzyme that degrades proteins, and the bacteria use them to colonise the host and to survive in its tissues. However, they are also essential for pathogenicity and destroy brain tissue. The team found that levels of gingipains co-localised with tau pathology, an indicator of cognitive impairment. In vitro, gingipains were shown to degrade tau protein, which can trigger tangle formation, and to be toxic to neurons. Moreover, when they orally infected mice with P. gingivalis, they found the bacteria spread to the brain, and caused increased production of the 42 amino acid form of amyloid-beta (Aβ1-42), which contributes to plaques.
The complexity of the disease should not be underestimated, we are still a long way off a cure.
The team synthesised molecules that were designed to inhibit gingipains. When administered to mice with AD, the load of P. gingivalis decreased in the brain, the production of Aβ1-42 was blocked, neuroinflammation was lessened, and hippocampal neurons were rescued. In fact, a phase 1 clinical trial with COR388, a bacterial protease inhibitor, showed it to be safe and well tolerated in both healthy and AD subjects. The trial found some improvements in the symptoms of the diseased patients compared to placebo controls, though phase 2 clinical trials, which should commence this year, will be testing the efficacy of the inhibitors. As well as helping to prove a causative effect of gingipains, these studies could provide potential new treatments for those suffering from AD. Vaccines against P. gingivalis are also under development and present a promising avenue for prevention.
The suggestion that P. gingivalis directly causes AD is not met without criticism. Robert Moir, a neurobiologist at the Boston based Massachusetts General Hospital is sceptical, “I’m fully on board with the idea that this microbe could be a contributing factor. I’m much less convinced that [it] causes Alzheimer’s disease”. He thinks that other pathogens may also contribute to the disease; especially as P. gingivalis was not found in all patients with AD. Pathogens including the spirochete bacteria associated with Lyme disease and some herpesviruses have also been found in the brains of AD patients, and it was suggested a few years ago that amyloid proteins themselves could act as infectious agents and spread via doctors’ surgery scalpels because they are resistant to disinfectants such as formaldehyde.
Although the link between gum disease and AD is becoming clearer and more convincing, other causes should not be overlooked, and the complexity of the disease should not be underestimated, we are still a long way off a cure. Nevertheless, it is probably better to be safe than sorry and get flossing!
Image Credit: U.S army graphic