Researchers have succeeded, for the first time, in developing a laboratory culture system that reproduces the full course of events underlying the development of Alzheimer’s disease. Using this system, HMS investigators from the Genetics and Aging Research Unit at Massachusetts General Hospital have provided clear evidence supporting the hypothesis that the deposition of beta-amyloid plaques in the brain is the first step in a cascade leading to the devastating neurodegenerative disease. They also identified the essential role of an enzyme, which, if inhibited, could be a therapeutic target.
“The amyloid hypothesis has 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 the inflammation leading to a vicious cycle of massive cell death,” says Rudolph Tanzi, the Joseph P. and Rose F. Kennedy Professor of Child Neurology and Mental Retardation at HMS, director of the Genetics and Aging Research Unit at Mass General, and co-senior author of the report. The paper appeared in the November 13, 2014, issue of Nature.
“One of the biggest questions since then has been whether beta-amyloid actually triggers the formation of the tangles that kill neurons. In this ‘Alzheimer’s-in-a-dish’ system, we’ve been able to show that amyloid deposition is sufficient to lead to tangles and subsequent cell death.”
Genetics and Aging Research Unit investigator Doo Yeon Kim, an HMS assistant professor of neurology at Mass General and 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 Mass General team used a gel-based, three-dimensional culture system to grow human neural stem cells that carried variants in two genes known to underlie early-onset familial Alzheimer’s disease (FAD).
After six weeks, the FAD-variant cells were found to have significant increases in both the typical form of beta-amyloid and the toxic form associated with Alzheimer’s. The variant cells also contained neurofibrillary tangles. Blocking formation of amyloid plaques also prevented the formation of the tangles, confirming amyloid’s role in the process. The version of tau found in tangles is characterized by the presence of excess phosphate molecules. When the team investigated ways of blocking tau production, they found that inhibiting the action of an enzyme 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 system can be adapted to other neurodegenerative disorders and could revolutionize drug discovery in terms of speed, costs, and physiologic relevance to disease,” says Tanzi. “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 patients with Alzheimer’s.”
Image: Leonard Lessin/Science Source