Periodic Reporting for period 1 - INFLAMM-ALZ (The Role of Neuroinflammation in Alzheimer’s Disease) Reporting period: 2017-11-01 to 2019-10-31 Summary of the context and overall objectives of the project Alzheimer’s disease (AD) is a major public health problem with substantial economic and social impacts around the world. With the development of diagnostic methods future patients can potentially be identified decades before they exhibit any symptoms. This makes it possible to treat future AD patients earlier, if curative treatments were available. However, we are still lacking therapies for AD that can prevent or attenuate the disease progress. The classical neuropathological hallmarks of AD include aggregation of amyloid β (Aβ) peptides into plaques in the brain, as well as the presence of neurofibrillary tangles composed of hyperphosphorylated tau protein. However, increasing evidence suggests that brain-specific macrophages, i.e. microglia, play a critical role in the pathogenesis of AD. The microglial cells are thought to be both protecting as well as mediators of neurodegeneration in AD. Being able to phagocytose and degrade toxic proteins, they might prevent the aggregation of Aβ plaques, but when activated, they could lead to ongoing, chronic inflammatory events contributing to the degradation of the brain. To be able to make use of the inflammatory system and microglia for the development of future AD therapeutics, we need to increase our understanding of the normal and pathological functions of these cells. The main project objective was to provide an in-depth understanding of how microglia contribute to the pathogenesis of AD, with focus on Aβ toxicity, memory impairment and microglia function. This project is a large interdisciplinary collaborative effort involving well-established methods such as confocal imaging and transgenic zebrafish, with newly developed photopharmacological tools. Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far In this study, we have made use of newly developed tools to manipulate signaling pathways of microglia cells in transgenic zebrafish embryos and larvae, providing means to follow their innate functions such as phagocytosis and morphology in real-time. The acquired data indicate that inhibiting microglial signaling pathways in healthy animals might not necessarily disturb normal embryonic development or neuronal functions. However, our data point towards the fact that inhibition of specific signaling pathways gives rise to different results in the presence of a neurotoxic insult.The acquired results in the project have open up for new concepts and theories regarding microglia function in neurodegenerative diseases that we will pursue in the future. In particular, our data point towards the importance of neurodegenerative cues for the recruitment and functionality of microglia cells, indicating that the theory of neuroinflammatory balance for maintenance of cognitive and brain functions is valid. Moreover, we believe that our research has provided a useful toolbox for studying neuroinflammation in the zebrafish, allowing for high resolution in space and time, valuable for analyzing other biological mechanisms involving toxic proteins, such as proteinopathies. We predict that the findings from this project will help explain the neuropathological mechanisms of neurodegeneration and AD. The data is currently evaluated in relation to clinical projects in the lab making use of AD patient cohorts, evaluating the genetic and neuropathological contribution to neuroinflammation in AD patients. Together with the findings from the current project, the target genes will be evaluated as risk genes for AD and in the development of future biomarkers for AD diagnostics and therapeutic interventions.Project data will be further validated in ongoing and future experiments in the lab, and will be the basis of future peer-reviewed research publications, as well as provide data for future applications for additional research grants. Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far) The lack of treatments of age-related disorders, such as AD, is a global challenge today with the increased life expectancy. This means that neurodegenerative diseases will be more common with an aging population. The lack of therapeutics for these disorders is already a serious problem to society, to individuals and their families. At the same time, there has been little success in developing efficient drugs that prevent AD progression.Understanding the signals and events that initiates AD will be crucial both for future drug discovery, as well as the development/refinement of diagnostic methods. The fact that microglia activation is thought to precede the common hallmarks of AD, i.e. both plaques and tangles, presents an opportunity to diagnose and prevent disease progression at an early stage. Moreover, as microglia show dynamic features, there are possibilities to manipulate their function to prevent, dampen and treat neurodegenerative damages in the brain. Therefore, manipulation of neuroinflammation and microglia function provides new possibilities to treat neurodegenerative diseases such as AD. However, we still lack a substantial amount of information regarding the early signals inducing the AD and the pathways that maintain the disease progression. Our hope is that the current project has provided important new knowledge that can help bring the field of neurodegeneration forward. We foresee that the knowledge from our studies will help understand new molecular targets for future development of biomarkers, brain imaging probes, and therapeutics. Combining the experimental analyses from the current project withour ongoing clinical project and industry collaborations will help drive this process. Finally, since microglia dysfunction and neuroinflammation are common in a variety of other conditions and diseases, such as neurodevelopmental disorders, autoimmune conditions, epilepsy, stroke, neuropathic pain, and cancer, we believe that the findings from our project will have a major impact on the advancement of other areas where microglia are contributing to the pathogenesis.