Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis are characterized by the deposition of insoluble protein aggregates. In addition, neuro-inflammatory processes, in particular microglial activation, are key pathological features of these disorders. While microglial activation is a necessary and neuroprotective response to tissue damage, it has been proposed that chronic neuroinflammation is detrimental to neurons and may contribute to the progression of disease. One potential mechanism by which microglia may be continuously activated is through contact with protein aggregates. Protein aggregates, such as amyloid fibrils, are protease-resistant and possess repetitive structures that may be immunologically mistaken for patterns found in bacterial cell walls. In this review, we will explore the downstream consequences of the interaction of protein aggregates with microglia, and how this has potential to shape the inflammatory landscape.