Growing "Alzheimer's in a dish" reveals new potential treatment target
The human brain is a complicated piece of machinery, which makes it difficult to untangle illnesses like Alzheimer's. To improve our understanding and find new potential ways to treat the disease, researchers at Massachusetts General Hospital (MGH) have now produced one of the most detailed models of "Alzheimer's-in-a-dish," using cultures of human neural cells that display neuroinflammation, a key element of the disease.
This isn't the first time a model of Alzheimer's has been grown in the lab. Back in 2014, the MGH team cultivated human neural cells that carried genes associated with familial Alzheimer's disease, then used a gel-based system that induced these neurons to develop tangles and amyloid-beta plaques, which are implicated in the disease. But that model doesn't capture the full story.
"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, co-senior author of the 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.'"
To do so, the team repeated the experiment inside a microfluidic device developed at the University of North Carolina. This device is made up of two circular chambers, one inside the other, and neural cells with a genetic predisposition towards familial Alzheimer's were cultured in the inner chamber. After a few weeks, the neurons and other cells were found to have higher levels of amyloid-beta and tau – proteins that contribute to the neurodegenerative disease. They also had more inflammatory factors, one of the culprits behind neuroinflammation.
Then, the researchers added human microglia to the outer chamber. As the immune cells of the nervous system, the microglia were quickly activated in response to the proteins in the inner chamber's neurons and began to migrate inwards. Once inside the inner chamber, the microglia began attacking the neurons, damaging vital structures and raising levels of inflammatory factors. After six days, 20 percent of the neurons and support cells had died as a result.
Having observed this Alzheimer's-in-a-dish play out, the team may have uncovered new ways to fight back, which is good news, given that the long-held belief that targeting the plaques themselves is currently being questioned after a string of failures in clinical trials.
"We also found that blocking two receptors in microglial cells – interferon receptor gamma and toll-like receptor 4 – could prevent neuroinflammation, which opens up new opportunities for drug discovery," says Tanzi. "This system should help us better understand the timeline by which these pathological events lead to dementia and enable us to screen for drugs that stop plaque deposition, tangle formation, and the resultant neuroinflammation."
The research was published in the journal Nature Neuroscience.