Important New Insights into Alzheimer's Disease from Cultured Adult Induced Stem Cells from Alzheimer's Patients

When you take skin cells from an Alzheimer's patient, and turn them into neurons in culture, you can study these "Alzheimer's neurons" in detail in the lab. This ability to work with cultured human Alzheimer neurons from induced stem cells, on a day to day basis, will give scientists an intimate familiarity with the genetic and biochemical differences which lead to the pathological changes in the disease. And none too soon, because as western societies grow older, Alzheimer's is threatening to bankrupt their social medicine services.

The feat, published in the January 25 online edition of the journal Nature, represents a new and much-needed method for studying the causes of AD, a progressive dementia that afflicts approximately 5.4 million Americans. More importantly, the living cells provide an unprecedented tool for developing and testing drugs to treat the disorder.

“We’re dealing with the human brain. You can’t just do a biopsy on living patients,” said Goldstein. “Instead, researchers have had to work around, mimicking some aspects of the disease in non-neuronal human cells or using limited animal models. Neither approach is really satisfactory.”

Goldstein and colleagues extracted primary fibroblasts from skin tissues taken from two patients with familial AD (a rare, early-onset form of the disease associated with a genetic predisposition), two patients with sporadic AD (the common form whose cause is not known) and two persons with no known neurological problems. They reprogrammed the fibroblasts into induced pluripotent stem cells (iPSCs) that then differentiated into working neurons.

The iPSC-derived neurons from the Alzheimer’s patients exhibited normal electrophysiological activity, formed functional synaptic contacts and, critically, displayed tell-tale indicators of AD. Specifically, they possessed higher-than-normal levels of proteins associated with the disorder.

With the in vitro Alzheimer’s neurons, scientists can more deeply investigate how AD begins and chart the biochemical processes that eventually destroy brain cells associated with elemental cognitive functions like memory. Currently, AD research depends heavily upon studies of post-mortem tissues, long after the damage has been done.

“The differences between a healthy neuron and an Alzheimer’s neuron are subtle,” said Goldstein. “It basically comes down to low-level mischief accumulating over a very long time, with catastrophic results.”

The researchers have already produced some surprising findings. “In this work, we show that one of the early changes in Alzheimer’s neurons thought to be an initiating event in the course of the disease turns out not to be that significant,” Goldstein said, adding that they discovered a different early event plays a bigger role.

The scientists also found that neurons derived from one of the two patients with sporadic AD exhibited biochemical changes possibly linked to the disease. The discovery suggests that there may be sub-categories of the disorder and that, in the future, potential therapies might be targeted to specific groups of AD patients.

Though just a beginning, Goldstein emphasized the iPSC-derived Alzheimer’s neurons present a huge opportunity in a desperate fight. _UCSD

This research is geared specifically toward Alzheimer's disease research, since Alzheimer's patients are the donours of the original cells being used. But the same approach can be used to culture a wide range of induced cell types, from patients with a wide range of disease types. In other words, this is just the beginning of a beautiful approach to bringing the full dynamics of human diseases into the laboratory for thorough study.

There is no way of predicting what possibilities may arise from this research over the long run.