Cell Culture Model of Alzheimer's First to Recapitulate Key Physiology

By Bio-IT World Staff

October 13, 2014 | A new model of Alzheimer's disease, created at the Genetics and Aging Research Unit of Massachusetts General Hospital, is the first to recreate both of the major features that the amyloid hypothesis predicts are central to the disease's symptoms: "plaques" of beta-amyloid protein, and "tangles" of a phosphorylated version of the tau protein. The model, which consists of human neurons grown in a three-dimensional culture, is thought to be physiologically very similar to the brain of an Alzheimer's patient. The research is published in this week's Nature by senior authors Doo Yeon Kim and Rudolph Tanzi, the latter of whom is known for his previous discovery of three genes linked to a hereditary form of Alzheimer's, together known as the FAD genes.

Tanzi, Kim and colleagues created the new model by growing human embryonic stem cells, containing mutations to two of the three FAD genes, in a gel culture with chemicals that stimulate stem cells to differentiate into neurons. After several weeks, the cells had formed a 3D neural network containing both plaques and tangles. The development of these structures lends new support to the amyloid hypothesis, which holds that an excess of beta-amyloid outside of cells is the fundamental cause of the disease. While the FAD mutations directly explain a buildup of beta-amyloid, the tangles of tau protein appear to be a secondary response to the presence of amyloid plaques.

A New York Times article already hails this disease model as a "breakthrough" in Alzheimer's research, quoting experts like P. Murali Doraiswamy of Duke University, who was not involved in the study, as saying, "It is a giant step forward for the field." The most commonly used models, FAD-mutant mice, have shown distressingly little correlation with the human disease in the twenty years they have been in regular use, leading to repeated failures of seemingly promising drugs in clinical trials. The Times reports that Tanzi now plans to test over 6,000 drugs on his Alzheimer's model in the hope that it will better correspond to a true human response.

It should be noted, however, that while the amyloid hypothesis is broadly favored, it has not been conclusively proven, and there have been persistent concerns in the neurological disease community that some other mechanism may be the true causative root of Alzheimer's. Additionally, attempts to create cultures from the cells of actual Alzheimer's patients have never reproduced the physiological features associated with the disease. While there is real cause for optimism that the new model by Tanzi and Kim accurately recreates the key parts of the disease progression, it is also possible that the reliance on FAD mutations and the beta-amyloid pathway misses some essential feature of Alzheimer's pathology. The disorder is notorious for a disconnect between preclinical models and the actual human disease, for reasons that remain mysterious.

With luck, the more complete expression of the amyloid hypothesis provided by the new 3D cell culture model will help to overcome some of the barriers to drug development in Alzheimer's. Tanzi, Kim and colleagues have already reported a successful reduction in tau protein tangles in their model using the enzyme GSK-3, and plan to continue testing drug responses and disruption of cellular pathways in their model.