Modeling Alzheimer’s: The neuronal code is finally cracked

A comprehensive 3D model of human neuronal pathophysiology leading to Alzheimer’s disease is now complete. The final model provides confirmation of how amyloid plaque build-up and tau neurofibrillary tangles are not just related to onset of disease, but that amyloid hastens tau pathology, according to a letter published online Oct. 12 in Nature.

Se Hoon Choi, PhD, a research fellow in neurology at Massachusetts General Hospital, and colleagues detailed how all the pieces fit together. The triumph follows a dogged search to find an appropriate model using animal neuronal cell models, which until now provided a clear picture of amyloid pathology, but tau pathology never seemed to fit into the schema. The report notes how FAD genetic mutations in amyloid precursor protein and presenilin 1 can create significant amyloid plaque. The 3D model of cells expressing FAD mutation were seen as resistant to the brain’s normal clean up crew and immunoelectron microscopy was able to pick up filamentous tau, and tau aggregates in both neurites and the soma.  

The researchers produced human neural progenitor cells by creating overexpression of human beta-amyloid precursor protein, or APP, and PSEN1 with FAD mutations. They also tested amyloid inhibition with beta- or gamma-secretase inhibitors and glycogen synthase kinase 3 (GSK3). Results of these investigations show potential for depressing amyloid build-up and moderating tau pathology.

“Our unique strategy for recapitulating Alzheimer’s disease pathology in a 3D neural cell culture model should also serve to facilitate the development of more precise human neural cell models of other neurodegenerative disorders,” wrote Choi et al. The model could also be used as a research tool for elucidating more information about the underpinnings of the amyloid-tau connection.