Image: Wikimedia Amyloid plaques, which deposit around nerve cells, and neurofibrillary tangles, which build up inside the cells, are the primary hallmarks of Alzheimer’s disease. Many researchers believe that the plaques trigger a cascade of events leading to disease pathology but, although this hypothesis is supported by animal studies, it has not been conclusively proved in humans. Amyloid deposition has also been suggested to lead to neuroinflammation, creating a positive feedback loop resulting in further amyloid accumulation and chronic inflammation. Polymorphisms leading to increased levels of interleukin-6 (IL-6), a pro-inflammatory cytokine which activates microglial cells, have been linked to Alzheimer’s disease, adding weight to this hypothesis.
Scientists at the Mayo Clinic were carrying out experiments to demonstrate that activated microglia exacerbate neurodegeneration when they discovered, unexpectedly, that the microglia cleared the plaques from the brain. They had believed that the microglia would be unable to clear the plaques and that the resulting inflammation would worsen the disease. To examine the effect of IL-6 on amyloid processing and deposition, the team over-expressed murine IL-6 (mIL-6) in the brains of transgenic mice expressing mutated forms of the human amyloid precursor protein. Instead of creating a neurotoxic feedback loop that exacerbated amyloid pathology, IL-6 had no effect on amyloid processing and enhanced plaque clearance.
The study, which was published online on October 14th in the FASEB Journal, is the first to examine in detail the effect of mIL-6 on amyloid deposition in vivo and suggests that the use of inflammatory mediators to manipulate the immune response could lead to new therapeutic approaches for the treatment of neurodegenerative diseases such as Alzheimer’s disease.
A study by researchers at the Universities of Florida and Frankfurt, published earlier this year in the journal Acta Neuropathologica, also addressed the role of microglia in Alzheimer’s disease. The study showed that microglia in amyloid-laden, degenerating regions of the brains of Alzheimer’s disease patients are not activated but, instead, are senescent and dystrophic. The team suggest that loss of microglia may contribute to neurodegeneration and that finding ways to keep microglia alive and healthy would be better than trying to inhibit their function with anti-inflammatory drugs.