An activation of the immune system is part of most neurological diseases, and the development of late-onset Alzheimer’s disease (AD) has been linked to mutations in immune-related genes. In addition, environmental and life-style factors that induce peripheral inflammation (such as infections, diabetes or obesity) significantly increase the risk for developing AD. This indicates a significant contribution of immunity to AD pathogenesis. The immune response during AD is largely driven by the brain’s resident macrophages, the microglia, which are attracted to and surround Aß deposits in the AD brain. However, various aspects of the microglial role in AD pathogenesis remain unclear.     

We have previously found that microglia are capable of “remembering” inflammatory insults, i.e. microglia show adaption of their immune responses to subsequent stimuli for extended periods of time. Importantly, we found that these long-term adjustments in microglial immune responses had significant effects on brain pathology in mouse models of AD pathology and stroke. Moreover, we could demonstrate that this adaptive response is based on epigenetic reprogramming of microglial cells. Thus, our results indicate that microglia can integrate different inflammatory stimuli over long periods of time, with significant effects on brain disease (Wendeln et al., Nature, 2018). This was the first description of how “innate immune memory” affects brain disease and may explain how inflammatory conditions in human patients (such as infections, diabetes or obesity) can increase the risk to develop Alzheimer’s disease or can modify the progression of neurodegenerative disease pathology. Thus, our results highlight innate immune memory as a previously unrecognized non-genetic risk factor for neurodegenerative diseases (Neher and Cunningham, Trends in Immunology, 2019).

Given the now well-appreciated heterogeneity of virtually all brain cell types, we have recently optimised methods to profile either enriched microglia or all non/neuronal brain cells in post-mortem mouse and human brain tissue at single cell level. In particular, we have adapted the so-called SHARE-seq method to profile not only the transcriptomic but also the epigenetic profiles from the very same cell (Scholz et al., Meth Mol Biol, 2023). Notably, our initial data indicate that combining epigenetic and transcriptional profiling may provide enhanced resolution of microglial subtypes both in mouse and human brain, likely driven by the additional information contained within the epigenome, e.g. cis-regulatory regions such as enhancers, which are crucial for macrophage identity and function (Scholz et al., Immunological Reviews, 2024). This method is now enabling us to perform in-depth analyses on how peripheral inflammation affects the brain and may lead to adaptive cellular responses in all brain cell types both in mouse models as well as human tissue, ensuring translatability of our findings.

Our main research objectives are:

1. To investigate how peripheral inflammatory stimuli affect the brain‘s immune response, how they induce innate immune memory, and how immune memory in turn affects neurodegenerative disease pathology and aging.
2. To understand how microglia contribute to AD pathology and in particular to amyloidosis and the resulting neuronal damage.
3. To understand microglial heterogeneity in neurodegenerative diseases and aging, the molecular pathways that drive transition from one microglial subtype to another, and which microglial subtypes may play pathological roles.

In addition to our work on microglia, we have also developed a strong interest in vascular dysfunction and pathology, which is now recognised as an important and early factor in AD pathogenesis and an independent contributor to cognitive decline. In this context, we focus on vascular amyloid and in particular, medin. Medin amyloid was discovered 25 years ago and is the most common human amyloid as it is found in the arteries of virtually every person over 50 years of age, but was largely ignored as it had not previously been linked to any disease.

            In two studies, our group recently provided mechanistic evidence that medin does not only cause age-associated arterial stiffening in the brain (Degenhardt, et al., PNAS, 2020) but also promotes vascular Aβ deposition and damage of the blood vessels in Alzheimer patients (Wagner et al., Nature, 2022). Notably, independent genetic analyses published around the same time confirm a possible role of medin amyloid as a crucial driver of cardiovascular aging. Because vascular pathology is a major contributor to age-related mortality and morbidity and because vascular dysfunction is now also recognised as an early indicator and mediator of cognitive decline in Alzheimer patients, medin amyloid may be a previously unrecognised therapeutic target (as summarized in Madine et al., Nature Aging, 2023). As treatments that specifically aim to restore vascular health and function during aging and Alzheimer’s disease currently do not exist, developing therapeutics to remove medin could benefit millions of people every year. This is a major focus of our current work.

Our main research objectives are:

1. To understand how medin drives vascular dysfunction during aging and AD.
2. To investigate whether genetic mutations in MFGE8, which have been found to be protective against cardiovascular disease, may act through affecting medin generation and aggregation.
3. To examine if medin amyloid could be a specific fluid biomarker for CAA,
4. To test if medin amyloid is a therapeutic target for restoring or preventing vascular dysfunction during brain aging and AD.