New evidence indicates that plaque forming amyloid beta has antibiotic properties and protects against brain infections, suggesting Alzheimer’s is either a dysregulated inflammatory response, or a reaction to infection
Investigators from Massachusetts General Hospital have investigated amyloid beta’s (Aβ) antimicrobial action in living models for the first time. The latest study builds on previous work which revealed Aβ’s surprising antimicrobial properties, and additional groups have since proved synthetic Aβ even inhibits viral invasion.
“Neurodegeneration in Alzheimer’s disease has been thought to be caused by the abnormal behavior of A-beta molecules, which are known to gather into tough fibril-like structures called amyloid plaques within patients’ brains. This widely held view has guided therapeutic strategies and drug development for more than 30 years, but our findings suggest that this view is incomplete”
What did they find out?
Transgenic mice expressing human Aβ survived significantly longer after salmonella infection than those without, and those mice lacking an amyloid precursor protein too fared even worse. Furthermore, C. elegans expressing the protein were similarly protected, and cultured neuronal cells were shielded from Candida. Curiously, the human Aβ appeared to be far more potent against infection than the previously studied synthetic version.
A logical step
This might seem like a radical concept, considering the past dogma in Alzheimer’s research, but when you look at Aβ’s behaviour it starts to make sense. Small peptides of Aβ can oligomerise to form the characteristic plaques seen in Alzheimer’s disease, but other well characterised antimicrobial proteins (AMPs) frequently use similar mechanisms; clumping and trapping invaders for clearance. Aβ’s ability to form these aggregated fibrils was shown to effectively capture microbes in both mouse and C. elegans.
“AMPs are known to play a role in the pathologies of a broad range of major and minor inflammatory disease; for example, LL-37, which has been our model for A-beta’s antimicrobial activities, has been implicated in several late-life diseases, including rheumatoid arthritis, lupus and atherosclerosis. The sort of dysregulation of AMP activity that can cause sustained inflammation in those conditions could contribute to the neurodegenerative actions of A-beta in Alzheimer’s disease”
This study alongside a recent assortment of studies raises some intriguing questions. While there is some data suggesting that Alzheimer’s could be a result of infection, there are probably many factors involved. It could be that this inflammatory reaction is a response to an increasing infectious burden, or it could be as a result of a large combination of factors influenced by the aging process.
“While our data all involve experimental models, the important next step is to search for microbes in the brains of Alzheimer’s patients that may have triggered amyloid deposition as a protective response, later leading to nerve cell death and dementia. If we can identify the culprits — be they bacteria, viruses, or yeast — we may be able to therapeutically target them for primary prevention of the disease”
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