BOSTON—Alzheimer's disease is characterized by a number of physiological issues, chief among them the development of amyloid plaques and neurofibrillary tangles that lead to the memory loss that is characteristic of the disease. But one of the key questions of Alzheimer's—which development comes first, the plaques or the tangles—has remained something of a 'chicken and the egg' issue until now. In an attempt to create a more accurate model of Alzheimer's disease in the human brain, a paper from investigators at Massachusetts General Hospital (MGH) has confirmed a longstanding theory regarding the order of events that cause the disease.
Doo Yeon Kim, Ph.D., an investigator in the Genetics and Aging Research Unit and co-senior author of the paper, realized that the two-dimensional models and animal models labs usually used weren't an effective representation of a human brain. Existing mouse models of Alzheimer's disease with the gene variants that lead to early-onset familial Alzheimer's disease (FAD) develop the hallmark amyloid plaques and memory issues, but the neurofibrillary tangles that strangle nerve cells and lead to cell death are not seen. In other models, the tangles appear, but plaques do not develop. As noted in the paper, “However, to date, no single disease model has serially linked these two pathological events using human neuronal cells.” That the existing models consistently fail to produce both the tangles and plaques that appear in human patients hinted at an issue in the current approach.
“Originally put forth in the mid-1980s, the amyloid hypothesis maintained that beta-amyloid deposits in the brain set off all subsequent events – the neurofibrillary tangles that choke the insides of neurons, neuronal cell death and inflammation leading to a vicious cycle of massive cell death,” Rudolph Tanzi, Ph.D., director of the MGH Genetics and Aging Research Unit and co-senior author of the report, explained in a statement. “One of the biggest questions since then has been whether beta-amyloid actually triggers the formation of the tangles that kill neurons. In this new system that we call ‘Alzheimer’s-in-a-dish,’ we’ve been able to show for the first time that amyloid deposition is sufficient to lead to tangles and subsequent cell death.”
In light of the inability of two-dimensional models to produce both plaques and tangles, the MGH team turned to a gel-based, 3D culture system. They used the 3D system to grow human neural stem cells with variants in two genes: the amyloid precursor protein and presenilin 1, both of which were discovered in the Tanzi laboratory and are known to contribute to FAD.
Six weeks later, the cells displayed significant increases in both standard beta-amyloid and the toxic form linked with Alzheimer's, and they also presented with the neurofibrillary tangles. The team found that by blocking steps that are pivotal for amyloid plaque formation, tangles were also prevented from forming. In addition, by blocking tau production with the enzyme GSK3-beta, which phosphorylates tau in human neurons, they were able to prevent tau aggregate and tangle formation, even when amyloid plaques were present.
“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,” said Tanzi. “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. 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.”
The paper, “A three-dimensional human neural cell culture model of Alzheimer’s disease,” was published in Nature Oct. 12.