Scientists from the University of California, San Diego School of Medicine, have created stem cell-derived, in vitro models of sporadic and hereditary Alzheimer’s, using induced pluripotent stem cells from patients with the neurodegenerative disorder. This experiment provides the ability to study the precise abnormalities present in neurons that cause the pathology of this neurodegenerative disease.
Senior study author Lawrence Goldstein, PhD, professor in the Department of Cellular and Molecular Medicine, Howard Hughes Medical Institute investigator and director of the UC San Diego Stem Cell Program, noted that the production of highly purified, functional human Alzheimer’s neurons in culture has never been done before. Goldstein said: “It’s a first step. These aren’t perfect models. They’re proof of concept. But now we know how to make them.”
This experiment represents a new method for studying the causes of Alzheimer’s disease. These living cells provide a tool for developing and testing drugs to treat the disorder. According to Goldstein, “We’re dealing with the human brain. You can’t just do a biopsy on living patients. 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 skin cells called fibroblasts from skin tissues from two patients with familial Alzheimer’s disease. They also used fibroblasts from two patients with sporadic Alzheimer’s disease, and two persons with no known neurological problems. They reprogrammed the fibroblasts into induced pluripotent stem cells (iPSCs) that then differentiated them into working neurons. These iPSC-derived neurons from the Alzheimer’s patients exhibited normal electrophysiological activity, formed functional synaptic contacts and displayed tell-tale indicators of Alzheimer’s disease. Also, they possessed higher-than-normal levels of proteins associated with Alzheimer’s disease.
With cultured neurons from Alzheimer’s patients, scientists can more deeply investigate how Alzheimer’s disease begins and chart the biochemical processes that eventually destroy brain cells and produce degeneration of elemental cognitive functions like memory. Currently, Alzheimer’s research depends heavily upon autopsies performed after the patient has died and the damage has been done. Goldstein added, “The differences between a healthy neuron and an Alzheimer’s neuron are subtle. It basically comes down to low-level mischief accumulating over a very long time, with catastrophic results.”
Neurons derived from one of the two patients with sporadic Alzheimer’s disease showed biochemical changes possibly linked to the disease. Thus there may be sub-categories of the disorder and, in the future, potential therapies might be targeted to specific groups of Alzheimer’s patients.