Stem cell technology has facilitated the development of human cell culture models of disease that can be used to study pathogenesis and test therapeutic candidates. These models hold particular promise for complex neurological diseases such as Alzheimer’s disease (AD) because existing animal models have been unable to fully recapitulate all aspects of pathology. We recently reported the design and characterization of a novel three-dimensional (3D) culture system that exhibits key events in the pathogenic cascade of AD, including extracellular aggregation of amyloid β peptides and accumulation of hyperphosphorylated/aggregated tau protein. Here we provide instructions for the generation and analysis of 3D human neural cell cultures, including the production of genetically modified human neural progenitor cells (hNPCs) with familial AD (FAD) mutations, the differentiation of the hNPCs in a 3D Matrigel matrix, and the analysis of AD pathologenesis in this model. The same principles may be applicable to models of other inherited neurodegenerative diseases characterized by the aberrant aggregation of misfolded proteins.
