According to a study by scientists published in the journal "Nature", inflammatory mechanisms caused by the brain's immune system drive the progression of Alzheimer's disease. These findings, which rely on a series of laboratory experiments, provide new insights into pathogenetic mechanisms that are believed to hold potential for tackling Alzheimer's before symptoms manifest.
Alzheimer's disease is a devastating neurodegenerative condition ultimately leading to dementia. An effective treatment does not yet exist. The disease is associated with the aberrant aggregation of small proteins called "Amyloid-beta" (Abeta) that accumulate in the brain and appear to harm neurons. In recent years, studies revealed that deposits of Abeta, known as "plaques", trigger inflammatory mechanisms by the brain's innate immune system. However, the precise processes that lead to neurodegeneration and progression of pathology have thus far not been fully understood.
"Deposition and spreading of Abeta pathology likely precede the appearance of clinical symptoms such as memory problems by decades. 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 manifest," says a senior researcher.
Previous work by the group that was published in Nature in 2013, had 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 in the murine model. NLRP3 is a so-called inflammasome that triggers production of highly pro-inflammatory cytokines. Furthermore, upon activation, NLRP3 forms large signaling complexes with the adapter protein ASC, which are called "ASC specks" that can be released from cells. "The release of ASC specks from activated cells has so far only been documented in macrophages and their relevance in disease processes has so far remained a mystery," says another author.
In the current study, it was demonstrated that ASC specks are also released from activated immune cells in the brain, the "microglia". Moreover, the findings provide a direct molecular link to classical hallmarks of neurodegeneration. "We found that ASC specks bind to Abeta in the extracellular space and promote aggregation of Abeta, thus directly linking innate immune activation with the progression of pathology," author says.
Authors show that intrahippocampal injection of ASC specks resulted in spreading of amyloid-β pathology in transgenic double-mutant APPSwePSEN1dE9 mice. By contrast, homogenates from brains of APPSwePSEN1dE9 mice failed to induce seeding and spreading of amyloid-β pathology in ASC-deficientAPPSwePSEN1dE9 mice. Moreover, co-application of an anti-ASC antibody blocked the increase in amyloid-β pathology in APPSwePSEN1dE9 mice.
This view is supported by a series of experiments in mouse models of Alzheimer's disease. In these, the researchers investigated the effects of ASC specks and its component, the ACS protein, on the spreading of Abeta deposits in the brain.
"Additionally, analysis of human brain material indicates at several levels that inflammation and Abeta pathology may interact in a similar fashion in humans. Together our findings suggest that brain inflammation is not just a bystander phenomenon, but a strong contributor to disease progression," author says. "Therefore, targeting this immune response will be a novel treatment modality for Alzheimer's."
https://www.dzne.de/en/about-us/public-relations/news/2017/press-release-no-24.html
https://www.nature.com/articles/nature25158
Inflammation drives progression of Alzheimer's
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