For the first time scientists have created stem cell-derived, in vitro models of sporadic and hereditary Alzheimer’s disease (AD), using induced pluripotent stem cells from patients with the neurodegenerative disorder.
Led by researchers at the University of California, San Diego School of Medicine, US, the study represents “a new and much-needed method” for studying the causes of AD, the authors reported in the journal Nature.
“Creating highly purified and functional human Alzheimer’s neurons in a dish – this has never been done before,” said senior study author Dr Lawrence Goldstein, PhD, Director of the UC San Diego Stem Cell Programme.
“It’s a first step. These aren’t perfect models, they’re proof of concept. But now we know how to make them. It requires extraordinary care and diligence, really rigorous quality controls to induce consistent behaviour, but we can do it.”
Dr 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; and two 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 displayed tell-tale indicators of AD. Specifically, they possessed higher-than-normal levels of proteins associated with the disorder, the authors reported.
“With the in vitro Alzheimer’s neurons, we 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,” they wrote.
“The differences between a healthy neuron and an Alzheimer’s neuron are subtle,” said Dr Goldstein.
“It basically comes down to low-level mischief accumulating over a very long time, with catastrophic results.
“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,” Dr Goldstein said, adding that they discovered a different early event plays a bigger role.
