A pathological hallmark of many neurodegenerative diseases is the presence of protein aggregates. Transgenic mice that recapitulate this pathology are a valuable resource to isolate these proteins for detailed study. One aspect of our research program is to characterize and quantify aggregates beta-amyloid (Abeta) peptides, superoxide dismutase 1 (SOD1), and huntingtin (htt) that comprise pathologic lesions found in Alzheimer's disease, familial amyotrophic lateral sclerosis, and Huntington's disease, respectively. In this chapter, we describe methods, based on sequential detergent extraction and ultracentrifugation, to isolate and analyze these protein aggregates. These methods have been applied to human tissues to some extent, but have been highly useful in studies involving transgenic mouse models of these diseases.