Intracellular assembly of filamentous inclusions in selected neuronal groups constitutes a defining pathology of many neurodegenerative disorders including Alzheimer?s disease and Parkinson?s disease. Formation of such inclusions, consisting of cellular proteins that exhibit aberrant modifications and altered physicochemical attributes, has been found to correlate with the duration and severity of cognitive impairment. How and why such filamentous inclusions evolve in progressive neurodegeneration remains unclear at present, but cellular and animal models can help us delineate its underlying mechanism. By incorporating epitope tagging and construction of novel minigenes in a sequential transfection strategy, we have succeeded in generating conditional transfectants of human neuronal lineage whose transgene overexpression leads to effective recapitulation of the cardinal features associated with neurofibrillary tangles and Lewy bodies. Utility of such cellular models will permit elucidation of the molecular and cellular mechanisms underlying how the filamentous inclusions evolve and, most importantly, provide us with a cost-effective, cell-based means to perform high-throughput screening of chemical libraries and develop rational therapeutics for progressive neurodegeneration.