- MIT research reveals new insights into cellular and circuit vulnerabilities in Alzheimer’s disease.
- The study also identified factors that may help prevent cognitive decline, including key brain cells and diet.
- This analysis highlights the relationship between cellular responses and cognitive resilience and offers new avenues for therapeutic strategies..
A new study has been published.
In this study, the researchers used a novel method to compare gene expression in different regions of the brains of people with and without Alzheimer’s disease.
Although brain cells share the same DNA, their identity and activity differ depending on gene expression patterns.
The researchers analyzed gene expression in more than 1.3 million cells from more than 70 different cell types across six brain regions from 48 tissue donors, 26 of whom had Alzheimer’s disease 22 did not.
Co-Senior Author Tsai Lai-huiThe Picower Professor of Neuroscience at MIT and director of the Picower Institute for Learning and Memory and the Aging Brain Initiative, explained the key findings: Today’s Medical NewsThe study states that it “identified pathways associated with cellular vulnerability and cognitive resilience.”
“These findings provide new targets for therapeutic intervention,” Professor Tsai explained.
“The cell types that show the most vulnerability (brain depletion) are located in the brain regions most important for supporting learning and memory (the entorhinal cortex and hippocampus), and these cells share a marker called Reelin. Also, metabolic pathways in a particular type of glial cell, namely astrocytes, are particularly perturbed in Alzheimer’s disease. Furthermore, how astrocytes express genes in the biosynthesis of antioxidants, choline, and polyamines appears to influence an individual’s resilience to dementia.”
— Professor Tsai Lai-hui
The researchers analyzed brain samples from the prefrontal cortex, entorhinal cortex, hippocampus, anterior thalamus, angular gyrus, and middle temporal cortex.
They observed thousands of subtle but important biological changes, cell by cell, gene by gene, in response to Alzheimer’s pathology.
By linking this information with a patient’s cognitive status, we can understand how cellular responses correlate with cognitive decline or resilience, which may suggest new treatments for cognitive decline.
Because pathology can appear 10 or more years before dementia symptoms, it may not be possible to address pathology at that stage, but it may be possible to protect cellular pathways that support cognitive function.
David Merrill“This study identified 76 brain-region-specific cell types that reveal cellular vulnerability, response and resilience to Alzheimer’s disease,” said Dr. Schneider, MD, a geriatric psychiatrist and director of the Pacific Brain Health Center at the Pacific Neuroscience Institute at Providence Saint John’s Health Center in Santa Monica, California, who was not involved in the study.
“This study paves the way for early detection and targeted therapeutic intervention, the long-held promise of precision medicine approaches,” he said.
Some of the earliest signs of amyloid pathology and neuronal loss in Alzheimer’s disease appear in memory-centered regions such as the hippocampus and entorhinal cortex.
The researchers identified a potential reason: Alzheimer’s disease patients have a greater reduction in one type of excitatory neuron in the hippocampus and four types of excitatory neurons in the entorhinal cortex compared with non-Alzheimer’s disease patients.
People who had these neurons depleted scored significantly worse on cognitive assessments.
Many of these vulnerable neurons are part of a common neural circuit and either directly express proteins or
These findings highlight particularly vulnerable neurons that share both neural circuits and molecular pathways, the loss of which leads to cognitive decline.
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The study found that cognitive decline was associated with a decrease in Reelin-producing neurons.
Analysis of human brain tissue and Alzheimer’s disease model mice confirmed a decrease in Reelin-positive neurons, highlighting the role that Reelin plays in brain health and the potential loss of Reelin in Alzheimer’s disease patients.
The researchers aimed to understand why Some people maintain good cognitive function Despite the presence of brain changes associated with Alzheimer’s disease.
They focused on the genes, cells and brain regions associated with this cognitive resilience.
The researchers found that in several brain regions, a type of brain cell called astrocytes, which are involved in antioxidant activity, choline metabolism and polyamine biosynthesis, are essential for maintaining cognitive function despite high levels of harmful tau and amyloid proteins.
The findings of this study are:
Additionally, the study highlighted the dietary supplement spermidine for its possible anti-inflammatory effects, although further research is needed.
By examining samples of brain tissue, the team found that people with greater cognitive resilience had higher levels of certain genes in astrocytes, supporting the predictions of their single-cell RNA analysis.
The researchers developed a new method to process huge amounts of single-cell data by grouping related genes into “gene modules.”
This approach uses coordinated patterns of gene expression, just as human movement involves coordinated joint actions.
This method helps to make more reliable inferences by analyzing groups of functionally related genes.
The researchers hope to use this method to make further discoveries and study the regulatory mechanisms of these genes, in order to find ways to reverse the progression of Alzheimer’s disease.
Dr Merrill added: “This study highlights the complexity of Alzheimer’s disease and the importance of different cell types in the brain’s response to the disease. Increasing public awareness of these mechanisms will help better recognize and manage Alzheimer’s.”
