Neurodegenerative diseases are recognized as the most common form of dementia
A study conducted by researchers at the Massachusetts Institute of Technology (MIT) uncovers how certain cells and circuits become vulnerable to and resilient to cognitive decline despite obvious pathological signs of Alzheimer’s disease (AD).
Published in NatureThe researchers used single-cell RNA profiling to measure differences in gene expression in more than 1.3 million cells of more than 70 cell types across six brain regions, including the prefrontal cortex, entorhinal cortex, and hippocampus, from 48 tissue samples provided by Rush University’s Religious Communities Study and the Rush Memory and Aging Project. Of the 48 tissue samples, 26 individuals had died with a diagnosis of AD and 22 had died without a diagnosis.
Today, AD, the most common form of dementia, is a neurodegenerative disease that impairs the brain’s memory and thinking abilities.
The researchers found that while people with AD had significantly fewer excitatory neuron types in the hippocampus and four in the entorhinal cortex and performed significantly worse on cognitive assessments than people without AD, some neurons either directly expressed a protein called Reelin, an extracellular glycoprotein that works with receptors to control cell migration, or were directly mediated by Reelin signaling, highlighting vulnerable neurons whose loss is associated with cognitive decline.
To confirm their results, the researchers examined human brain tissue samples and the brains of two AD model mice, and found that the entorhinal cortex in both humans and mice had a significant reduction in Reeling-positive neurons.
Furthermore, the team found that astrocytes across multiple brain regions express genes related to antioxidant activity, choline metabolism, and polyamine biosynthesis, which are associated with sustained cognitive performance in the presence of elevated levels of tau and amyloid, and noted that spermidine, a molecule found in dietary supplements, may have anti-inflammatory properties.
“Combining this information with a patient’s cognitive status could help us understand how cellular responses relate to cognitive decline or resilience and suggest new ways to treat cognitive decline,” said co-author Manolis Kelis, professor of computer science and head of the Computational Biology Group at MIT.
