We established a unique platform for proteomic analysis of cultured three-dimensional (3D) neurons and brain tissue from Alzheimer's disease (AD) patients. We collected peripheral blood mononuclear cells (PBMC), converted PBMC to induced pluripotent stem cell (iPSC) lines, and differentiated the iPSC into human 3D neuro-spheroids. The postmortem brain tissue from the superior frontal cortex, inferior frontal cortex and cerebellum area of the AD patients was compared to the same regions from the control subjects. Proteomic analysis of 3D neuro-spheroids derived from AD subjects revealed the alteration of a number of proteins involved in axon growth, mitochondrial function, and antioxidant defense. Similar analysis of post-mortem AD brain tissue revealed significant alteration in proteins involved in oxidative stress, neuro-inflammation, along with proteins related to axonal injury. These results clearly indicate that the dysfunction of 3D neurons from AD patients in our in vitro environment is comparable to the post-mortem AD brain tissue in vivo. In conclusion, our study revealed a number of candidate proteins that have important implications in AD pathogenesis and supports the notion that the iPSC-derived 3D neuronal system functions as a model to examine novel aspects of AD pathology. Significance: In this study, we present a unique platform for proteomic analysis of induced pluripotent stem cell-derived three dimensional (3D) neurons and compare the results to those from three regions of post-mortem brain tissue from Alzheimer's disease patients and normal control subjects. Our results show that the dysfunction of 3D neurons from AD patients in our in vitro environment is comparable to the post-mortem AD brain tissue in vivo. Our results revealed several candidate proteins that have important implications in AD pathogenesis.
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