Study shows inflammation may lead to spread of Alzheimer’s plaques
Discovery points to potential target for therapeutics before memory loss occurs
Douglas T. Golenbock, MD
New research by UMass Medical School scientist Douglas T. Golenbock, MD, the Pillar Chair in Biomedical Research, professor of medicine and microbiology & physiological systems and chief of the Division of Infectious Disease and Immunology, and colleagues at the University of Bonn in Germany, provides a link between innate immune-activated inflammation and Alzheimer’s disease that possibly explains how the disease spreads through the brain. The paper, published Dec. 20 in Nature, points to an accumulation of multiprotein complexes that act as seeds for the accumulation and spread of Alzheimer’s-causing plaques.
The research provides new insight into pathogenic mechanisms that are believed to hold potential for the mechanism-based treatment of Alzheimer’s disease before symptoms manifest. Senior author Michael T. Heneka, MD, adjunct professor of medicine at UMass Medical School and a senior researcher and director of neurodegenerative diseases and gerontopsychiatry at the University of Bonn, envisions that one day this may lead to new ways of treating the 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 one in 85 people will suffer from Alzheimer’s disease. There is currently no treatment that halts or limits the progression of the disease.
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.
“Deposition and spreading of amyloid beta pathology likely precedes the appearance of clinical symptoms such as memory problems by decades,” said Dr. Heneka. “Therefore, a better understanding of these processes might be a key for novel therapeutic approaches. Such treatments would target Alzheimer’s at an early stage, before cognitive deficits appear.”
Previous research conducted by Heneka and Golenbock established that the molecular complex NLRP3, which is an innate immune sensor, is activated in brains of Alzheimer’s patients and contributes to the pathogenesis of Alzheimer’s. An inflammasome, NLRP3 triggers production of highly proinflammatory cytokines.
Activation of NLRP3 results in the formation of large signaling complexes with the adapter protein ASC, which are called “ASC specks,” that can be released from cells. Until now, the release of ASC specks from activated cells has been only been documented in immune cells called macrophages—not in other tissues.
Investigations by Heneka and Golenbock showed that ASC specks are also released from activated immune cells in the brain called microglia. These ASC specks bind to amyloid beta protein and promote aggregation of plaques. This provides a direct molecular link between innate immune activation and the hallmarks of neurodegeneration, according to Heneka.
“At some point, if enough of these ASC complexes accumulate in sufficient quantities, they further activate inflammasomes and more specks form and enhance the formation of amyloid beta plaques,” said Golenbock “The more specks you get, the more inflammation occurs and these specks act as seeds for the accumulation and spread of amyloid beta protein plaques.”
“Our findings suggest that brain inflammation is not just a bystander phenomenon, but a strong contributor to disease progression,” Heneka said. “Therefore, targeting this immune response will be a novel treatment modality for Alzheimer’s.”
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