Building on their development of the first culture system to replicate fully the pathology behind Alzheimer’s disease, a Massachusetts General Hospital (MGH) research team has now produced a system that includes neuroinflammation, the key biological response that leads to the death of brain cells. The investigators describe their system, which incorporates the glial cells that that not only surround and support neurons but also provide some immune system functions, in a paper published in Nature Neuroscience. “Our original ‘Alzheimer’s in a dish’ system recapitulated the plaques and tangles typically seen in the brains of patients with Alzheimer’s disease, but did not induce neuroinflammation,” says Rudolph Tanzi, director of the Genetics and Aging Research Unit in the MassGeneral Institute for Neurodegenerative Disease (MIND) and co-senior author of the current paper. “Studies have shown that we can have many plaques and tangles in our brains with no symptoms, but when neuroinflammation kicks in, exponentially more neurons die and cognitive impairment leading to dementia is induced. A complete model of Alzheimer’s pathology needs to incorporate that ‘third leg of the stool.’”
In their 2014 Nature paper, the MGH team described using a gel-based, 3-D culture system – developed by Doo Yeon Kim of the Genetics and Aging Unit, also a co-senior author of the current study – to induce the formation of both amyloid-beta plaques and neurofibrillary tangles in human neural cells carrying gene variants associated with early onset, familial Alzheimer’s disease (FAD).
That study confirmed that amyloid deposition was the essential first step leading to the formation of tangles containing the pathogenic form of the protein tau. The updated system also brings in technology developed by co-senior author Hansang Cho, now of the University of North Carolina, Charlotte, when he was a postdoctoral fellow in the MGH BioMEMS Resource Center.