Study reveals new factors of vulnerability and resilience to Alzheimer’s

The most detailed study of brain cell gene expression to date has revealed critical vulnerability and resilience factors in Alzheimer’s disease. Alzheimer’s.

Genomic and laboratory analysis of more than 1.3 million cells of more than 70 types corresponding to 6 brain regions from 48 tissue donors, 26 of whom died with a diagnosis of Alzheimer’s and 22 without, has revealed the key role of a protein called reelin in the cognitive weaknessand that of a nutrient (choline) in maintaining it.

Advances in single-cell microscopy

The study, led by researchers at the Massachusetts Institute of Technology (MIT) and published in the journal Nature, has been possible thanks to a new single-cell analysis and visualization tool that they have published in open access so that it is available to other researchers.

With less powerful microscopes, the scientist who gives his name to the disease, Aloais Alzheimer, More than a century ago, he discovered the first two regions of the brain affected by the neuronal alteration caused by the hippocampus and the entorhinal cortex, the guardians of memory and orientation.

“Where Alzheimer saw plaques of amyloid protein, our single-cell microscope tells us, cell by cell and gene by gene, about thousands of subtle but important biological changes in response to the disease,” notes one of the authors, Manolis Kellisa computational biology researcher at MIT.

“Connecting this information to the cognitive status of patients reveals how cellular responses relate to cognitive loss or recovery ability, and may help propose new treatments,” he adds.

The key role of reelin

These single-cell resolution microscopes have made it possible to determine a possible cause of the deterioration: the lowest abundance of a hippocampal neuron and four entorhinal cortex neurons. People who suffered from Alzheimer’s showed a lack of these neurons compared to those who did not.

They also found that these vulnerable neurons are interconnected in a common circuit, and that they express a protein called reelin, the loss of which has been associated in previous research with a reduction in cognitive ability. “We can infer that reelin has a protective or beneficial effect on the brain and that the loss of the neurons that produce it is associated with cognitive decline,” says one of the authors, MIT neuroscientist, Li-Huei Tsai.

On closer analysis, the researchers found that specifically vulnerable neuron subtypes were also involved in reelin signaling, further reinforcing the molecule’s importance.

To confirm their hypothesis, the researchers compared the data obtained from human brain tissue samples with those from two types of Alzheimer’s model mice, and found a reduction in reelin-producing neurons in humans and mice with the disease.

Resilience factors

The study has also offered valuable clues about which factors can preserve cognition. Its results indicate that in several brain regions, good cognitive development It is associated with correct levels of astrocytes, star-shaped cells that hold nerve cells in place and help them function properly.

The results reinforce those of previous research led by Tsai and fellow MIT researcher, Susan Lundqvist, who suggested that a dietary supplement of choline (a key nutrient for cognitive development) helps astrocytes cope with the most significant Alzheimer’s risk gene alteration.

The antioxidant findings also point to a molecule that can be provided through dietary supplements, spermidine, which has anti-inflammatory properties beneficial for improving cognitive ability.

In addition to single-cell analysis, the researchers made direct observations on the brain tissue of the samples, confirming that those individuals with better cognitive recovery had a greater expression of several of the genes expressed by astrocytes.