New research has shed light on the progression of Alzheimer’s disease, revealing how different brain cells contribute to the spread of tau protein pathology. The study, which analysed multiple datasets of mouse models, has identified key cell types linked to vulnerability and resilience in the disease. These findings, published in the journal Communications Biology, could inform future efforts to slow or even halt the progression of Alzheimer’s.
Alzheimer’s disease is characterised by the accumulation of tau protein in the brain, forming tangles that contribute to cognitive decline. However, the disease does not affect all brain regions equally, and scientists have long sought to understand why certain areas are more vulnerable. Ashish Raj, PhD, professor of radiology at the University of California, San Francisco, explained the motivation behind the study: “It remains a mystery why certain parts of the brain, like the limbic system, are especially vulnerable to Alzheimer pathology, while others, like the neocortex, stay resilient. Our motivation was to understand why this happens by looking for the underlying cell type composition of the vulnerable or resilient brain regions. Our reasoning is that selective vulnerability or resilience must be underpinned by cell types or molecular factors.”
Researchers used a novel computational approach to map the distribution of cell types across the brain and compared these with the progression of tau pathology. The findings indicate that hippocampal glutamatergic neurons are particularly susceptible to tau accumulation, while cortical glutamatergic and GABAergic neurons appear to resist its spread. Raj highlighted a key finding: “We found that indeed many cell types have strong positive correlation with tau, most prominently the glutamatergic cells residing in the entorhinal cortex and hippocampus. There is something special about these cells in these areas, as similar cells in other neocortical areas do not show this correlation with tau.”
Oligodendrocytes, the cells responsible for producing myelin, emerged as the most resilient cell type, suggesting they may play a protective role against tau-driven neurodegeneration. Raj elaborated on this observation: “Another intriguing finding was that oligodendrocytes, a type of cell whose role is in the maintenance and repair of the myelin sheath surrounding axons, is strongly negatively correlated with tau. This suggests that perhaps this type of cell plays a protective role in the disease process.”
One of the key insights from the study is that the presence of tau pathology does not necessarily correlate with the locations of known Alzheimer’s risk genes. This suggests that cell-type-specific characteristics, such as their function and connectivity, may be more important in determining regional vulnerability. The researchers found that microglia, the brain’s immune cells, are consistently associated with tau pathology, reinforcing the idea that neuroinflammation plays a central role in disease progression.
The study also highlighted differences in how tau pathology spreads over time. Oligodendrocyte-rich areas displayed notable resistance to tau deposition, while microglia-dense regions showed higher susceptibility. This could mean that certain cell types influence tau aggregation, either accelerating or slowing its accumulation. Such insights could be crucial in identifying therapeutic targets that focus on altering the behaviour of these cells to mitigate the disease.
Another striking finding was the role of interneurons, particularly subtypes of GABAergic neurons, which were differentially affected by tau pathology. Some exhibited high vulnerability, while others showed resistance, hinting at complex interactions between neuronal circuits and the disease process. This selective vulnerability could help explain the varied cognitive symptoms seen in Alzheimer’s patients, depending on which regions and cell types are affected.
Although the study relied on mouse models, the researchers suggest that the principles of selective vulnerability are likely applicable to the human brain. Raj outlined the next steps: “These are very exciting results that will inform the field for years to come. In our own laboratory, we intend to perform a similar study in the human brain. It will be important to see that our conclusions hold in humans as well. We will also develop network models of how tau pathology spreads, and whether the cells we found in this study mediate that spread process in a meaningful way. Understanding how that mediation occurs may give us new therapeutic targets.”
