ALZHEIMER'S Disease is the most common form of dementia, affecting an estimated 30 million people worldwide. The cause of the condition is unknown, but the prime suspect is amyloid-beta (AÎ²), a 42-amino acid peptide which accumulates within neurons to form insoluble structures called senile plaques that are thought to be toxic. AÎ² is synthesized in all neurons; it is associated with the cell membrane, and is thought to be involved in cell-to-cell signalling, but its exact role has eluded researchers.
A new study published in the open access journal PLoS One now shows that AÎ² is a potent antibiotic that can prevent the growth of a number of disease-causing microbes. The study provides the first evidence of a normal role for AÎ², and also raises the intriguing possibility that Alzheimer's Disease occurs as a result of the immune system's response to infection. The findings could make researchers re-think Alzheimer's, and have implications for how the condition is treated.
Stephanie Soscia of Massachusetts General Hospital and her colleagues had previously observed that AÎ² shares a number of properties with a group of molecules called antimicrobial peptides. Also known as host defense peptides, these molecules are potent antibiotics that target a wide range of microbes. They are components of the innate immune system that forms the first line of defence against infection, and are of particular importance in the brain, which is impenetrable to the antibodies produced by the immune system elsewhere in the body.
To measure the antimicrobial activity of AÎ², the researchers grew 12 different micro-organisms in culture dishes, and added the synthetic or genetically engineered peptide to the cultures. All the microbes used in the study are common and cause infections in humans. They included Candida albicans, the yeast that causes oral and genital thrush, and the bacterium Streptococcus pneumoniae, which is one of several causes of meningitis. For seven of the microbes, the antibiotic activity of AÎ² was found to be equivalent to, and in some cases more potent than, known antimicrobial peptides such as Cathelicidin.
The researchers then tried to replicate these results in living tissue. Using brains from recently deceased Alzheimer's patients, they took samples from two regions which are affected differently by the disease: the temporal lobe, which degenerates first, leading to disorientation and memory loss, and which usually contains high levels of AÎ², and the cerebellum, which is affected only minimally and normally contains low AÎ² levels. The tissues were ground in a pestle and mortar to produce a homogeneous solution, which was then added to dishes containing the same microbes. In these experiments, the temporal lobe tissue effectively inhibited the growth of the microbes, but the cerebellar tissue did not. Furthermore, the antimicrobial activity of the temporal lobe tissue was significantly reduced by the addition of anti-AÎ² antibodies.
The findings suggest several possible mechanisms which could lead to Alzheimer's Disease. First, infection of the central nervous system could stimulate the innate immune system, causing AÎ² synthesis followed by its deposition in neurons. Indirect evidence for this comes from studies which show that the brains of Alzheimer's patients harbor microbes such as Chlamydia pneumoniae, a cause of pneumonia, Helicobacter pylori, which is associated with gastric ulcers and stomach cancer, and Borriela spirochetes, which causes Lyme Disease. A clinical trial also showed increased infection rates in patients taking the AÎ²-lowering drug tarenflurbil. A second possible mechanism is an on-giong immune response that occurs in response to a transient infection. Thirdly, the innate immune system could trigger an inappropriate inflammatory response in the brain, in the absence of any infection, or following a traumatic brain injury, stroke or some other insult to the brain.
The new study has several implications for the treatment of Alzheimer's. If AÎ² is indeed a component of the brain's innate immune system, then its deposition could be prevented or slowed down by pre-emptive attacks on microbes that would normally evoke a response. Researchers assume that AÎ² deposition is the underlying cause of Alzheimer's; many of the treatments being developed are based on this assumption, and are designed to clear the deposits. The new study suggests that this approach might leave patients susceptible to brain infections.
Not everyone is convinced that AÎ² is a component of the innate immune system, however. Norman Relkin, director of the memory disorders program at New York Presbytarian-Weill Cornell hospital, told the New York Times that although the idea is "unquestionably fascinating," the evidence for it is "a bit tenuous."
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Soscia, S., et al. (2010). The Alzheimer's Disease-Associated Amyloid Î²-Protein Is an Antimicrobial Peptide. PLoS ONE 5(3) DOI: 10.1371/journal.pone.0009505.
It was good to see this study which supports the ground breaking work done by Judith Miklossy http://www.miklossy.ch/401/index.html
With the controversy surrounding diagnosis and treatment of Lyme disease details can be seen on IDSA and www.ilads.org websites showing presentations to the panel reviewing the 2006 IDSA Lyme Disease guidelines, many valuable years of research no doubt will have been missed.
My 2006 publication (excerpt below) explicitly described AÎ² as an antimicrobial peptide based on its multiple similarities to melittin.
In addition, the described antimicrobial action was explicitly cited as a basis for AÎ² to be considered a component of the innate immune system, likely as a rapid response to infections by enveloped viruses such as HSV.
Excerpt from Kammerman et al., 2006:
"Numerous groups have reported that AÎ²42 can disrupt lipid membranes by creating pore-like holes (ion channels) within the membranes. This property of AÎ²42 appears to be related to an antimicrobial function; nature is replete with examples of peptide antimicrobials that effect their function through membrane disruption. In fact, some of these peptides show strong activity against HSV-1. For example, melittin, which has an Î±-helical amphipathic structure similar to AÎ²42, has anti-HSV activity. We assert that Î² amyloid, by virtue of its similar molecular shape and size, is a peptide antimicrobial component of the innate immune system which can neutralize enveloped viruses such as HSV-1. We contend accordingly that ion-channel pore formation in the HSV-1 envelope generated by AÎ²42 is virucidal."
Kammerman EM, Neumann DM, Ball MJ, Lukiw W, Hill JM. Senile plaques in Alzheimer's diseased brains: possible association of beta-amyloid with herpes simplex virus type 1 (HSV-1) L-particles. Med Hypotheses. 2006;66(2):294-9.