Proteins linked to Alzheimer’s disease –

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

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

The study, led by researchers at the Massachusetts Institute of Technology (MIT) and published in the journal “Nature”, has been made 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.

Using less powerful microscopes, the scientist who gives his name to the disease, Aloais Alzheimer, discovered more than a century ago 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’s 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 pathology,” said one of the authors, Manolis Kellis, a 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.

Single-cell microscopes have identified a possible cause of the decline: a lower abundance of one neuron in the hippocampus and four neurons in the entorhinal cortex. People with Alzheimer’s showed a deficiency in these neurons compared to those without.

They also found that these vulnerable neurons are interconnected in a common circuit and express a protein called reelin, the loss of which had 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 data 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 insights into which factors can preserve cognition.

Their results indicate that in several brain regions, good cognitive development is associated with correct levels of astrocytes, star-shaped cells that hold nerve cells in place and help them function properly.

The findings reinforce those of previous research led by Tsai and fellow MIT researcher Susan Lundqvist, which 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.