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Nov 06, 2014
 |  BC Innovations  |  Tools & Techniques

AD goes 3D

A 3D cell-based model that encapsulates the two hallmark features of Alzheimer's disease-neurofibrillary tangles and b-amyloid plaques-has been created by a team at Massachusetts General Hospital to help screen compounds for the disease.1Although the system goes far beyond existing in vitro models, scientists polled by SciBX disagree on whether it is close enough to the human disease to affect drug development.

More than a decade ago, a group from the University of California, Irvine developed a mouse model of Alzheimer's disease (AD) that includes both amyloid and neurofibrillary tangle pathology.2 But a reliable cell-based model would provide significant advantages for drug discovery by enabling more compounds to be rapidly screened.

Alan Snow, president, CSO and founder of ProteoTech Inc., told SciBX, "In animal models of Alzheimer's, it can take longer than a year to see disease pathology and then months or years to get data on the effects of a therapeutic candidate. If we could accelerate the initial screening in a cell model, we could get a better idea of how a drug works before the long trials in animals."

ProteoTech is developing several compounds to treat AD, including PeptiClere (DP-74), a b-amyloid (Ab)-targeting compound that is in preclinical testing.

Previous in vitro models of AD developed from cell lines or patient-derived neurons only captured the early features of the disease such as elevated Ab levels and did not replicate more advanced characteristics such as Ab deposition and neurofibrillary tangles.

Increased levels of Ab lead to aggregation of the protein and ultimately result in the formation of extracellular amyloid plaques in the brain. Those plaques are thought to be a major trigger of neurodegeneration.

The neurofibrillary tangles, by contrast, are associated with microtubule-associated protein-t (tau; MAPT; FTDP-17). Abnormal expression and increased phosphorylation of tau causes intracellular tau aggregation, leading to formation of neurofibrillary tau tangles that may also contribute to neuronal cell death.

The challenge, said Doo Yeon Kim, an assistant professor of neurology in MGH's Genetics and Aging Research Unit and at Harvard Medical School, has been that these disease features take too long to develop in vitro. "Human neural stem cell cultures can be differentiated and maintained for up to 120-180 days," he said. "In our opinion, this...

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