“Alzheimer’s-in-a-dish” will help accelerate drug discovery
Researchers in the US claim to have reproduced the sequence of molecular events that leads to nerve cell death in Alzheimer’s disease for the first time using a cell culture model.
The findings provide proof for the so-called amyloid hypothesis for AD, which holds that the amyloid plaques found in the brains of patients are directly involved in the development and progression of the disease, they say.
Neuroscientists Rudolph Tanzi and Doo Yeon Kim of Massachusetts General Hospital in Boston say the cell culture system can be used to study AD and new therapies designed to treat the disease in vitro, accelerating drug discovery and development. At the moment, new drugs are tested in mouse models that they suggest exhibit significant differences from AD in humans.
By growing neurons with genetic defects that leads to AD (amyloid precursor protein and presenilin 1) in a gel-like matrix, the researchers succeeded in reproducing the full course of events underlying the development of AD, including the formation of amyloid plaques and the tau protein tangles that are hallmarks of the disease.
They also report in the journal Nature that they have uncovered the first “clear evidence that deposition of beta-amyloid plaques in the brain is the first step in a cascade leading to the devastating neurodegenerative disease.”
The amyloid hypothesis has been dented by a series of failures among drugs targeting the formation of plaques in late-stage trials, leading to suggestions that either the treatments are being used too late in the course of the disease, or that amyloid is not a valid target at all. Other groups have suggested that addressing tau protein could be a better approach, for example.
“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,” says Tanzi.
“‘We’ve been able to show for the first time that amyloid deposition is sufficient to lead to tangles and subsequent cell death.” Mouse models of AD do not develop tangles, so have always been considered somewhat flawed in their ability to predict the efficacy of new therapies. Moreover, tests with anti-amyloid drugs indicate they can block the formation of both plaques and tangles in the cell culture model.
The researchers say they have also identified the essential role in that process of an enzyme, inhibition of which could be a therapeutic target, and plan to start a large-scale screening programme to test thousands of compounds for activity against it.
“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,” adds Tanzi.
“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.”
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