Plaques, Tangles Form on Cue in 3D Alzheimer’s Model

A model that promises to accelerate the development of Alzheimer’s treatments has already confirmed the amyloid hypothesis. The model has also alerted researchers to a protein that helps amyloid plaques progress to neurofibrillary tangles.

Called “Alzheimer’s in a dish” by its developers, the model is a gel-based, three-dimensional culture system. Unlike mouse models and liquid two-dimensional culture systems, the new model reproduces the full course of events underlying the development of Alzheimer’s disease. Crucially, the model produces both plaques and tangles.

This point was emphasized by the model’s developers, a team of scientists from the Genetics and Aging Research Unit at Massachusetts General Hospital. The scientists presented their findings October 12 in Nature, in an article entitled, “A three-dimensional human neural cell culture model of Alzheimer’s disease.”

While the mouse models of Alzheimer’s disease that express the gene variants causing the inherited early-onset form of the disease do develop amyloid plaques in their brains and memory deficits, the neurofibrillary tangles that cause most of the damage do not appear. Other models succeed in producing tangles but not plaques. Cultured neurons from human patients with Alzheimer's exhibit elevated levels of the toxic form of amyloid found in plaques and the abnormal version of the tau protein that makes up tangles, but not actual plaques and tangles.

“Testing drugs in mouse models that typically have brain deposits of either plaques or tangles, but not both, takes more than a year and is very costly,” said Rudolph Tanzi, Ph.D., director of the MGH Genetics and Aging Research Unit and co-senior author of the report. “With our three-dimensional model that recapitulates both plaques and tangles, we now can screen hundreds of thousands of drugs in a matter of months without using animals in a system that is considerably more relevant to the events occurring in the brains of Alzheimer’s patients.”

Genetics and Aging Research Unit investigator Doo Yeon Kim, Ph.D., co-senior author of the Nature paper, realized that the liquid two-dimensional systems usually used to grow cultured cells poorly represent the gelatinous three-dimensional environment within the brain. Instead the MGH team used a gel-based, three-dimensional culture system to grow human neural stem cells that carried variants in two genes—the amyloid precursor protein and presenilin 1—known to underlie early-onset familial Alzheimer's disease (FAD).

“The 3D-differentiated neuronal cells expressing FAD mutations exhibited high levels of detergent-resistant, silver-positive aggregates of phosphorylated tau in the soma and neurites, as well as filamentous tau, as detected by immunoelectron microscopy,” the authors of the Nature article wrote. “Inhibition of amyloid-β generation with β- or γ-secretase inhibitors not only decreased amyloid-β pathology, but also attenuated tauopathy. We also found that glycogen synthase kinase 3 (GSK3) regulated amyloid-β-mediated tau phosphorylation.”

Blocking steps known to be essential for the formation of amyloid plaques prevented the formation of the tangles, confirming amyloid’s role in initiating the process. The version of tau found in tangles is characterized by the presence of excess phosphate molecules, and when the team investigated possible ways of blocking tau production, they found that inhibiting the action of an enzyme called GSK3-beta—known to phosphorylate tau in human neurons—prevented the formation of tau aggregates and tangles even in the presence of abundant beta-amyloid and amyloid plaques.

“This new system, which can be adapted to other neurodegenerative disorders, should revolutionize drug discovery in terms of speed, costs, and physiologic relevance to disease,” asserted Dr. Tanzi.