An immune response is part of most neurological diseases, and the development of late-onset Alzheimer's Disease (AD) has been linked to immune related genes, indicating an important role of the immune system in this neurodegenerative disease. The major population of immune cells in the brain are microglia (brain macrophages), which are attracted to and surround Amyloid-β deposits in the AD brain. However, various aspects of the microglial role in amyloid plaque homeostasis and AD pathogenesis remain unclear.
We recently demonstrated that microglia are capable of retaining a long-lasting epigenetic memory of peripheral inflammatory insults, which are known risk factors for late-onset AD. Importantly, this epigenetic memory altered how microglia responded to much later developing AD pathology and, in turn, affected how AD hallmarks developed in mouse models. These findings indicated that microglia are capable of “innate immune memory” (Wendeln et al., Nature, 2018). We are actively working on understanding the mechanisms of microglial epigenetic reprogramming in response to peripheral inflammation by analysing mouse and human tissue on a single cell basis, and by studying its effects on different forms of neurodegenerative diseases.
Amyloids are proteins that form insoluble deposits in tissue, where they often lead to disruption of tissue function and disease. The best-known example is Amyloid-β, whose deposits in the brain are a cardinal feature of Alzheimer’s disease. However, we have recently found that the amyloid medin, which is the most common amyloid known in humans, accumulates in blood vessels in the periphery and brain and disrupts their function during ageing in the brain of mice (Degenhardt et al., PNAS, 2020). Because dysfunction of blood vessels is also an important contributor to AD and dementia, we are now working on understanding the role of medin in Alzheimer’s disease by studying mouse models as well as human tissue.
Thus, our main objective is to understand the pathogenic mechanism of Alzheimer’s disease and to develop new therapeutic interventions to treat this devastating disease.