We evaluate cellular prion protein (PrP(C)) immunoreactivity (IR) in Alzheimer's, Parkinson's, diffuse Lewy body, and motor neuron diseases (MND), progressive supranuclear palsy, and multiple system atrophy. We use immunohistochemistry for PrP, including five monoclonal antibodies against different epitopes and three different pretreatments, alpha-synuclein, phosphorylated tau, beta-amyloid, and ubiquitin. Disease-specific inclusions are devoid of PrP(C) IR. Using double immunofluorescence and confocal laser microscopy we observe focal overlapping of PrP(C) with tau and with alpha-synuclein in early, but not in fully developed inclusions. However, PrP(C) IR neurons may contain abnormal tau or alpha-synuclein aggregates. Additionally, we observe a loss of PrP(C) IR in anterior horn neurons in MND. Our results suggest that expression of PrP(C) reflects a general response to cellular stress rather than specific co-operation in aggregation of other proteins.