Max Planck Research Group Scheiblich

Normal brain ageing and neurodegenerative diseases share common pathological hallmarks such as loss of brain volume and cognitive decline following inflammation. While the mechanisms involved in age-related inflammation-driven changes to the brain remain poorly understood, activation of microglia appears to be an essential component.

Being the brain's primary innate immune cells, microglia contribute to cerebral homeostasis by sensing changes in their immediate environment, clearing cellular debris, providing neurotrophins, and protecting neurons from excessive activation. Microglia are highly dynamic and responsive cells that promptly respond to homeostatic changes. These changes may switch the function of microglia from housekeepers to adaptive responders. Age-related changes, however, can dramatically affect these microglial functions and may shift microglia into cellular senescence. The age-related senescent phenotype is characterized by profound modifications of their cellular functions, which compromise both their housekeeping and defensive tasks. In addition, senescent microglia acquire a specific pro-inflammatory senescence-associated secretory profile, which may affect neuronal functions such as information storage, memory formation, and neuronal regeneration. An imbalance in the inflammatory fine-tuning mechanism can give rise to CNS diseases and might shift the normal ageing process to a hazardous scenario of chronic inflammation in which neurodegeneration may occur.

The primary goal of our group is to understand the mechanisms within microglia that regulate brain homeostasis and the deviations observed during ageing, neurodegenerative conditions, and other brain disorders. Our research places a significant emphasis on uncovering the fundamental principles governing the interactions between microglia and neurons. Understanding these interactions is pivotal as they play a crucial role not only in normal ageing but also in the progression of neurodegenerative diseases.

Intercellular communication via tunneling nanotubes

The mechanisms contributing to brain ageing are largely unknown but may imply the induction of a feedback loop of multiple interacting cellular and molecular events leading to less efficient communication between brain cells. In keeping with this, we recently discovered a mechanism whereby microglia form tunneling nanotubes (TNTs), cellular protrusions connecting distant cells, with other brain cells (neurons and microglia) that suffer from the accumulation of cytotoxic protein aggregates. Importantly, we found that the formation of intercellular TNTs allowed the redistribution of cytotoxic protein aggregates to less burdened neighboring microglia, providing support for protein degradation (PMID: 34555357). Remarkably, when co-culturing burdened cells (neurons and microglia) with naïve microglia, we observed the horizontal transfer of functional intact mitochondria from microglia into burdened cells which vastly reduced oxidative stress and increased cellular health in the recipients. This mechanism aims to rescue burdened cells from their functional impairment and to improve cell survival. However, breakdown of this process and failure in the formation of microglial TNTs to neighboring cells, e.g., due to brain ageing or the presence of inflammatory events, may aggravate pathology leading to excessive cellular dysfunction and cell death. One of our goals is to understand the mechanisms that control TNT formation in the brain and to define their meaning in maintaining brain homeostasis.

Neuroinflammation and cellular senescence

A hallmark of brain ageing is the occurrence of inflammation. Evidence for such inflammatory events can not only be found in patients suffering from neurodegenerative diseases but also in healthy elderlies. It refers to a chronic inflammatory state (cellular senescence) that is associated with the dysregulated induction of inflammatory pathways, such as the NLRP3 inflammasome pathway (PMID: 37278117 and PMID: 34507948 and PMID: 31748742), the sustained release of pro-inflammatory molecules and the inability to proliferate in cells like microglia. Of interest, this chronic neuroinflammation is correlated with the impairment of appropriate microglial function, affecting their phagocytic and degradation capabilities, leading to the accumulation of damaged cellular debris and cytotoxic material in the brain. It further induces the release of neurotoxic factors, creating an unfavorable environment for neurons and elevating the risk for neurodegenerative processes. One of our goals will be to investigate the impact of age-related inflammatory events on microglial functions, such as phagocytosis and degradation, release of inflammatory mediators (cytokines/chemokines), mitochondrial functioning, and TNT formation and cargo transfer between interconnected cells. Understanding the link between inflammation and microglial impairment is crucial in deciphering the role of these cells in various age-related neurological disorders.

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