The Alzheimer's disease research community is nowadays ever more strongly considering chronic inflammation in the brain as a vital part of the progression of the condition. In the amyloid cascade hypothesis, a slow aggregation of amyloid-β over decades (for reasons that are debated) causes ever greater inflammatory dysfunction in microglia, the immune cells of the brain responsible for clearing up metabolic waste such as protein aggregates. That inflammation in turn sets the stage for tau aggregation to take place to a significant degree, causing cell death and severe neural dysfunction.
Today's open access research is an example of the sort of work taking place to better understand how amyloid-β interacts with microglia to produce the outcome of chronic inflammation. In principle at least, a better understanding usually leads to new targets for the development of drugs that can interfere in the process.
A great deal of hypothesizing takes place among Alzheimer's researchers. The animal models are highly artificial, and thus prone to misleading results, there is a great deal of dissatisfaction with the decades-long relentless focus on amyloid-β, and it is very costly to prove any particular point using human data and human patients. Theorizing is thus a great deal easier than validating any given hypothesis, and as a result there are are numerous variations on the basic idea that chronic inflammation is an important part of the progression of Alzheimer's disease. One faction sees rising levels of amyloid-β as only a side-effect of persistent infections (such as herpesvirus, lyme disease, and so forth), and it is the infection that produces lasting inflammation in brain tissue, and its downstream consequences. Another faction ties the new understanding of cellular senescence into the development of chronic inflammation in the brain. In the years ahead, these various views will eventually give way to a true understanding, as the state of the human evidence improves.
Alzheimer's disease is characterized by clumps of the protein Aß (amyloid beta), which form large plaques in the brain. Aß resembles molecules on the surface of some bacteria. Over many millions of years, organisms have therefore developed defense mechanisms against such structures. These mechanisms are genetically determined and therefore belong to the so-called innate immune system. They usually result in certain scavenger cells absorbing and digesting the molecule.
In the brain, the microglia cells take over this role. In doing so, however, they trigger a devastating process that appears to be largely responsible for the development of dementia. On contact with Aß, certain molecule complexes, the inflammasomes, become active in the microglia cells. They then resemble a wheel with enzymes on the outside. These can activate immune messengers and thereby trigger an inflammation by directing additional immune cells to the site of action.
"Sometimes the microglia cells perish during this process. Then they release activated inflammasomes into their environment, the ASC specks." These released specks take on a calamitous dual role: On the one hand, they bind to the Aß proteins and make their degradation more difficult. On the other hand, they activate the inflammasomes in even more microglia cells, and much more than Aß alone would do. During this process, more and more ASC specks are released. It thus adds fuel to the fire, as it were, and thereby permanently stokes up the inflammation.
Alzheimer's disease is the world's most common neurodegenerative disorder. It is associated with neuroinflammation involving activation of microglia by β-amyloid (Aβ) deposits. Based on previous studies showing apoptosis-associated speck-like protein containing a CARD (ASC) binding and cross-seeding extracellular Aβ, we investigate the propagation of ASC between primary microglia and the effects of ASC-Aβ composites on microglial inflammasomes and function. Indeed, ASC released by a pyroptotic cell can be functionally built into the neighboring microglia NOD-like receptor protein (NLRP3) inflammasome. Compared with protein-only application, exposure to ASC-Aβ composites amplifies the proinflammatory response, resulting in pyroptotic cell death, setting free functional ASC and inducing a feedforward stimulating vicious cycle. Clustering around ASC fibrils also compromises clearance of Aβ by microglia. Together, these data enable a closer look at the turning point from acute to chronic Aβ-related neuroinflammation through formation of ASC-Aβ composites.