[Points]
– Succeeded in reproducing the pathology of Alzheimer’s disease in a dish using patient iPS-derived neurons.

– The neurons of many Alzheimer’s patients regress from a mature state to an immature state.

– Mutation of PSEN1 gene changes chromatin structure that results in change of microRNA and gene expression levels.

Researchers believe this is a valuable model for new drug discovery for Alzheimer’s disease.

Alzheimer’s disease (AD) is a chronic and progressively worsening neurodegenerative disease of memory and cognitive loss that affects about 6% of people at age 65 or older. The causes of most AD cases are not well understood and no treatments have been found to stop the disease. However, in 5% of cases, known as familial early onset AD, changes have been identified in genes that are associated with disease onset in people around 40 years of age.

To address how neurons in patients with Alzheimer’s disease (AD) differ from neurons in healthy individuals, researchers at the University of California San Diego compared iPS-derived neurons from patients carrying mutations in one familial AD gene, PSEN1, with those from non-diseased patients.

With a renewable source of fresh neurons to perform multiple types of tests and analyses for changes in neuron gene regulation, they uncovered how several key genes, which normally regulate the structure of a neuron’s DNA, are dramatically altered. The researchers found that in the diseased neurons, some DNA regions that are normally open to activity are now closed, and vice versa. As a consequence, the AD neurons do not express their normal neuron gene maintenance programs and thus lose their neuronal identity, with a transformation toward an earlier pre-neuronal developmental state.

Remarkably, the molecular and cellular changes the researchers identified in the AD iPS-derived neurons showed substantial overlap with those found in a previous study of 600 brains from deceased AD patients with sporadic AD. This overlap between the new and previous results suggests there may be shared mechanisms underlying most Alzheimer’s disease cases at the cellular and molecular level that can be modeled with the iPS-derived neurons.

With a new model of AD in a dish, the researchers are now using the diseased neurons and the newly identified regulatory genes to develop new medicines to stop the progression of AD.

The team was led by Shankar Subramaniam, professor of bioengineering at the UC San Diego Jacobs School of Engineering. The findings are published Nov. 13 in Science Advances. Link to free copy of the article: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673760/