Role of microglia in amyloid beta-induced tau cross-seeding and spread

• Applicant: Dr. Christina Ising
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2017 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 392521896

Alzheimer's disease (AD) is associated with accumulation of amyloid-beta (abeta) in extracellular plaques and hyperphosphorylated tau in intracellular neurofibrillary tangles as well as chronic neuroinflammation. All of this taken together leads to progressive neuronal loss, ultimately resulting in cognitive decline and memory loss. Even though AD is the most common form of dementia worldwide, no cure or even disease-modifying treatment exists.According to the amyloid cascade hypothesis, tau pathology develops downstream of abeta plaque formation in AD but the mechanistic link between these two pathologies remains elusive. In line with the amyloid cascade hypothesis, tau seeding and spreading can be induced by fibrillar amyloid-beta, a mechanism known as cross-seeding. However, reducing amyloid plaque burden in patients does not seem to slow disease progression and tau pathology correlates much better with clinical symptoms. This suggest the involvement of another pathway in the development of AD. Research over the past years showed that the development of tau pathology is accelerated in the presence of reactive microglia, an essential player of the brain's own immune system. Conversely, microglia depletion leads to reduced tau spread from cell to cell. Interestingly, microglia are chronically activated during the progression of AD as they attempt to clear abeta from the brain. Therefore, we hypothesize that activated microglia play a role in the development of tau seeding and spreading downstream of amyloid-beta. To investigate this potential mechanism, we will first confirm an effect of activated microglia on tau spread. Second, we will analyze the effects of activated or depleted microglia on abeta-induced tau cross-seeding in different cell culture and mouse models. Third, we will study the role of the NLRP3 inflammasome, which controls the generation of pro inflammatory cytokines in microglia, by inducing tau cross seeding after genetic knockout of the inflammasome in mice. Last, we will determine if the presence of microglia from mice, that develop abeta pathology, are sufficient to induce tau pathology in cell culture and mouse models.Taken together, our approach could shed light on a long standing question in AD and could help to better understand disease development. This could ultimately lead to new treatment strategies by targeting the brain's over-reacting immune system.

• DFG Programme: Research Grants