The research noted here improves the understanding of how inflammation acts to drive the progression of Alzheimer's disease, despite being secondary to the well-known deposition of amyloid-β observed in the condition. Alzheimer's disease is considered to be in part an inflammatory condition. Rising levels of chronic inflammation occur with aging, in the brain and elsewhere in the body, and there is plenty of evidence for inflammation to contribute to a good many age-related conditions. The ordering of cause and effect in Alzheimer's is still somewhat up for debate, but there is evidence for the cascade to begin with amyloid-β, that then produces inflammation as the immune cells of the brain react to it, which in turn leads to tau aggregation. The paper here adds nuance to that possible ordering, suggesting that amyloid-β and inflammation form their own feedback loop, spurring one another forward.
The immune system of the central nervous system is its own creature, quite different in its details from the immune system of the rest of the body, and arguably much more integrated and necessary for the correct function of the brain than is the case in other organs. Nonetheless, similar classes of age-related dysfunction arise, and inflammation is one of the results regardless of protein aggregation such as the formation of amyloid deposits. Immune cells become overly active, but at the same time less effective at carrying out their assigned tasks. Inflammation is a necessary part of the immune response to many of the issues it might have to deal with, typically those that involve destruction, as as removal of senescent or potentially cancerous cells, and mounting attacks upon the pathogens that constantly try to invade the body and brain. If permanently switched on, however, inflammation begins to disrupt all of the other necessary tasks of the immune system, such as those relating to regeneration or shepherding the correct function of brain cells.
For a number of years now, some researchers have departed a little way from the mainstream focus on removal of amyloid-β to consider an anti-inflammatory approach to building therapies for Alzheimer's, but this line of research hasn't made a sizable impact yet. Reducing inflammation in a usefully targeted way is still quite challenging, as the immune system is very complex, though promising noises are emerging from research groups investigating NLRP3 as a target. That also happens to show up in the research here as a part of the connection between immune cells, amyloid, and inflammation.
A new study shows that inflammatory mechanisms caused by the brain's immune system drive the progression of Alzheimer's disease. In recent years, studies revealed that deposits of amyloid-β, 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. Previous work 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 a mouse 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.
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 amyloid-β in the extracellular space and promote aggregation of amyloid-β, thus directly linking innate immune activation with the progression of pathology." 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 amyloid-β deposits in the brain. "Additionally, analysis of human brain material indicates at several levels that inflammation and amyloid-β 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. Therefore, targeting this immune response will be a novel treatment modality for Alzheimer's."
The spreading of pathology within and between brain areas is a hallmark of neurodegenerative disorders. In patients with Alzheimer's disease, deposition of amyloid-β is accompanied by activation of the innate immune system and involves inflammasome-dependent formation of ASC specks in microglia. ASC specks released by microglia bind rapidly to amyloid-β and increase the formation of amyloid-β oligomers and aggregates, acting as an inflammation-driven cross-seed for amyloid-β pathology.
Here we 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-deficient APPSwePSEN1dE9 mice. Moreover, co-application of an anti-ASC antibody blocked the increase in amyloid-β pathology in APPSwePSEN1dE9 mice. These findings support the concept that inflammasome activation is connected to seeding and spreading of amyloid-β pathology in patients with Alzheimer's disease.