MIT study reveals how specific cells in AD become vulnerable and resilient

The neurodegenerative condition is recognised as the most common form of dementia

A study conducted by researchers at the Massachusetts Institute of Technology (MIT) has revealed how specific cells and circuits become vulnerable and resilient to cognitive decline in Alzheimer’s disease (AD), despite clear signs of disease pathology.

Published in Nature, researchers measured gene expression differences using single-cell RNA profiling in more than 1.3 million cells of over 70 different cell types in six brain regions, including the prefrontal cortex, entorhinal cortex and hippocampus, from 48 tissues donated by the Religious Order Study and the Rush Memory and Aging Project at Rush University, 26 of whom had died with an AD diagnosis and 22 of whom had not.

Currently the most common form of dementia, AD is a neurodegenerative condition that deteriorates the brain’s memory and thinking skills.

Researchers found that one type of excitatory neuron in the hippocampus and four in the entorhinal cortex were significantly less abundant in people with AD compared to people without and performed significantly worse in cognitive assessments, while several directly expressed a protein known as reelin, an extracellular glycoprotein that regulates cell migration in partnership with its receptors, or were directly mediated by reelin signalling, highlighting vulnerable neurons whose loss was associated with reduced cognition.

To check their results, researchers examined the human brain tissue samples and brains of two kinds of AD model mice. Results showed a significant reduction in reeling-positive neurons in both the human and mouse entorhinal cortex.

In addition, the team found that astrocytes across several brain regions expressed genes associated with antioxidant activity, choline metabolism and polyamine biosynthesis that were associated with sustained cognition, even amid high levels of tau and amyloid, and also pointed to a molecule that can be found as a dietary supplement, spermidine, which potentially may have anti-inflammatory properties.

Co-senior author Manolis Kellis, professor of computer science and head of MIT’s Computational Biology Group, commented: “Connecting this information with the cognitive state of patients reveals how cellular responses relate with cognitive loss or resilience, and can help propose new ways to treat cognitive loss.”