Neuroinflammation is how the immune system of the brain fights against diseases. As a natural defense mechanism, this reaction may harbor beneficial effects, but under circumstances not yet well understood, it may also have detrimental consequences for the brain and even contribute to the progression of the disease that initially stimulated the immune reaction. The present proposal will study the mechanisms by which neuroinflammation could transition from a beneficial to a detrimental outcome in preclinical models of Alzheimer’s disease (the most prevalent form of dementia), amyotrophic lateral sclerosis (the most common motor neuron disease), and septic encephalopathy (the leading cause of mortality in intensive care units), three diseases sharing a prominent inflammatory component. Moreover, it will aim to identify genetic factors marking the key steps of this transition, both in preclinical models and samples of patients suffering from the respective diseases, in order to find points of intervention for early diagnosis and development of better targeted and more efficient therapeutic strategies.