Scientists Engineer First Human Brain Cells with Alzheimer

Researchers from the Genetics and Aging Research Unit at Massachusetts General Hospital (MGH) have created what they Alzheimer's in a Dish - a petri dish with human brain cells that develop the plaques and tangles that are the hallmarks of Alzheimer's. Experts say this discovery may accelerate testing of new drugs to treat and prevent the disease.

The laboratory culture system has succeeded in reproducing the full course of events underlying the development of Alzheimer's disease, enabling investigators to provide the first clear evidence supporting the hypothesis that deposition of beta-amyloid plaques in the brain is the first step in a cascade leading to the devastating neurodegenerative disease. Using the system, they also identify the essential role of an enzyme in that process. If that enzyme can be inhibited, they can create a therapeutic target for Alzheimer's.

The researchers grew the brain cells in a gel, then added genes for Alzheimer's. The cells soon developed hard clumps known as plaques, and coils known as tangles -- both features of Alzheimer's that disrupt normal brain activity. The lead researcher believes that this breakthrough will help reduce the time and cost of drug development. Previously, researchers have had to study the disease in mice, a process that can be very time consuming. The new system can help scientists to test thousands of drugs in a matter of months and reduce the cost of testing.

According to Rudolph Tanzi, PhD, director of the MGH Genetics and Aging Research Unit and co-senior author of the report receiving advance online publication in Nature, "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. 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."

Mouse models of Alzheimer's disease that express the gene variants causing the inherited early-onset form of the disease develop amyloid plaques in their brains and memory deficits, but the neurofibrillary tangles that cause most of the damage are not present. Other models produce tangles but not plaques. In other experiments cultured neurons from human patients with Alzheimer's exhibit elevated levels of the toxic form of amyloid found in plaques and the abnormal version of the tau protein that makes up tangles, but not actual plaques and tangles. The team used a gel-based, three-dimensional culture system to grow human neural stem cells that carried variants in two genes -- the amyloid precursor protein and presenilin 1 -- known to underlie early-onset familial Alzheimer's Disease (FAD). Both of those genes were discovered in Tanzi's laboratory.

After the researchers grew the cells for six weeks, they showed significant increases in both the typical form of beta-amyloid and the toxic form associated with Alzheimer's. The toxic cells also had the neurofibrillary tangles that choke the inside of nerve cells causing cell death. By using blocking steps that are essential for the formation of amyloid plaques, the researchers prevented the formation of the tangles. Thus, they confirmed the role of amyloid in starting the process. The type of tau in tangles has excess phosphate molecules. When the team tried to block tau production, researchers discovered that inhibiting the action of an enzyme called GSK3-beta -- known to phosphorylate tau in human neurons -- stopped the formation of tau aggregates and tangles even in the presence of abundant beta-amyloid and amyloid plaques.