Alzheimer’s disease study identifies brain cells at higher risk of tau protein damage

Scientists have developed a powerful new tool to map different types of cells throughout the brain. Using this technique, researchers have discovered that specific brain cells crucial for memory, located in a region called the hippocampus, are especially susceptible to the protein buildup that characterizes Alzheimer’s disease. This finding, published in Nature Communications Biology, helps explain why Alzheimer’s disease damages memory so severely and opens new avenues for targeted treatments.

Alzheimer’s disease is a devastating brain disorder that progressively erodes memory and thinking abilities, and currently has no cure. A major characteristic of Alzheimer’s is the accumulation of a protein called tau within brain cells. This buildup is thought to disrupt normal cell function and contribute to the widespread brain damage seen in the disease.

Scientists have long observed that Alzheimer’s disease doesn’t affect the brain uniformly; some regions are hit harder and earlier than others. Understanding why some brain areas are more vulnerable than others is a significant question in Alzheimer’s research.

Researchers from The University of Texas at Arlington and the University of California–San Francisco sought to understand this selective vulnerability by examining different types of brain cells and their susceptibility to tau protein accumulation. They aimed to identify which specific cell types might be most at risk and to uncover the underlying reasons for this vulnerability.

To conduct their investigation, the research team employed a novel brain-mapping approach called Matrix Inversion and Subset Selection, or MISS. This technique allows scientists to create detailed maps showing the distribution of various types of brain cells throughout the entire brain. The researchers utilized a vast dataset that cataloged the genes active in approximately 1.3 million individual brain cells from mice.

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This dataset, created by the Allen Institute for Brain Science, provides a comprehensive profile of different cell types in the mouse brain. Using the MISS technique and this cellular data, the researchers generated maps showing where 42 distinct types of brain cells are located in the mouse brain. These cell types included various kinds of neurons, the primary signaling cells of the brain, as well as non-neuronal support cells.

To understand how these cell maps relate to Alzheimer’s disease, the team then compared these maps to data from previous studies that tracked the buildup of tau protein in the brains of mice that were genetically engineered to develop features of Alzheimer’s. By overlaying the cell type maps with the tau accumulation patterns, they could identify which cell types were present in brain regions most affected by tau protein.

The analysis revealed a clear pattern of vulnerability among different brain cell types. The researchers found that certain types of neurons located in the hippocampus, a brain region essential for memory formation, showed a strong association with tau protein buildup. These vulnerable neurons were specifically identified as glutamatergic neurons, a type of neuron that uses glutamate as its primary signaling molecule.

In contrast, neurons in the cortex, the outer layer of the brain responsible for higher-level functions like reasoning and sensory processing, were generally less associated with tau accumulation.

“Using mathematical and computational models, we found that certain cells in the hippocampus, a brain area important for memory and navigation, are more vulnerable to tau buildup,” said author Pedro Maia, an assistant professor of mathematics at UTA. “These glutamatergic neurons showed a strong connection with tau deposits, meaning they are more likely to be affected. In contrast, brain cells in the cortex—the part of the brain that controls movement, sensory information, emotions and reasoning—were less likely to be affected by tau.”

Interestingly, the study also highlighted the resilience of oligodendrocytes, a type of non-neuronal brain cell that produces myelin, a substance that insulates nerve fibers and helps them transmit signals efficiently. Oligodendrocytes showed a negative association with tau buildup, suggesting they might be less vulnerable or even play a protective role against tau accumulation.

Further analysis indicated that the distribution of different brain cell types across brain regions was a better predictor of where tau protein accumulates than the location of genes previously linked to Alzheimer’s disease. This suggests that the inherent cellular makeup of different brain areas, rather than just genetic predisposition, may be a primary factor determining their vulnerability to Alzheimer’s-related protein buildup.

“Overall, this study helps us understand why certain brain regions are more affected by tau buildup leading to Alzheimer’s disease,” Maia said. “By identifying the cell types and gene functions involved, our study showcases how theoretical and computational models can provide new insights into the progression of Alzheimer’s disease. This is another piece of valuable data that will help us specifically target the vulnerable cells and genes associated with tau buildup, potentially slowing or preventing Alzheimer’s disease progression in the future.”

The study, “Searching for the cellular underpinnings of the selective vulnerability to tauopathic insults in Alzheimer’s disease,” was authored by Justin Torok, Pedro D. Maia, Chaitali Anand, and Ashish Raj.