Scientists establish link between inflammatory process and progression of Alzheimer's disease

An international team of researchers from the University of Massachusetts Medical School, the University of Bonn and the Center for Advanced European Studies and Research in Germany have shown that a well-known immune and inflammatory process plays an important role in the pathology of Alzheimer's disease. This process, which results in the mature production of the pro-inflammatory cytokine called interleukin-1 beta (IL-1B) and is involved in the body's defense against infection, has also been established as a clinical target for rheumatoid arthritis. The finding, published in Nature, points to the possibility that drugs that disrupt the production of IL-1B, such as those for rheumatoid arthritis, may also prove beneficial for patients with Alzheimer's.

"This finding represents an important new clinical target for patients with Alzheimer's disease," said Douglas T. Golenbock, MD, chief of infectious diseases and immunology and professor of medicine and microbiology & physiological systems. "We've known for years that the plaques associated with Alzheimer's were surrounded by microglia, the resident immune cell of the central nervous system. What we didn't know was what role, if any, inflammation played in the progression of the disease. With this link we have a new path to potentially identifying and attacking this horrible disease."

The most common form of dementia, Alzheimer's is a degenerative neurological disorder that leads to memory loss, impaired cognitive function, and eventually death. By 2050 it is predicted that 1 in 85 people will suffer from Alzheimer's disease. There are no available treatments.

A key physiological component of Alzheimer's disease is the presence of extracellular plaques, primarily composed of beta amyloid peptides, which aggregate in the brain. These plaques are believed to be toxic and the chief cause of nearby neuron death and cortical material loss. The hippocampus, which plays an important role in short-term memory, is one of the first regions of the brain to suffer damage from Alzheimer's.

Golenbock and colleagues had established in previous studies that neurons in cell cultures died after nearby microglia cells, the main form of active immune defense in the brain and spinal cord, were exposed to amyloid beta fibrils, such as those found in Alzheimer's plaques. Typically, microglias are responsible for removing plaques, damaged neurons and infectious agents from the central nervous system. The beta amyloid peptide, however, generates inflammation in the central nervous system by activating microglia to produce neurotoxic compounds, including cytokines. How this process was being activated in patients with Alzheimer's disease, though, was unclear.

Earlier work done in the Golenbock laboratory demonstrated that beta amyloid peptide could induce the production of IL-1B by activating a multi-protein receptor complex in microglial cells known as the NLRP3 inflammasome. Because of its ability to sense the beta amyloid peptide, the NLRP3 inflammasome has been implicated in several chronic inflammatory diseases, including gout and asbestosis. Examining Alzheimer's tissue samples, scientists found that "every one of the cell samples contained increased evidence of activated inflammasomes, strongly suggesting that they were producing IL-1B," said Golenbock.