Novel Human Cell-Based 3D Model Provides Insights Into Alzheimer’s Disease
The model provides insights into the progression of AD and could help to accelerate the testing of new treatments.
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Researchers at Massachusetts General Hospital developed a 3D model to study Alzheimer's disease. They found that CT8+ T Cells exacerbate neurodegeneration by infiltrating the brain due to a CXCL10-CXCR3 pathway. Targeting this pathway could lead to novel Alzheimer's therapies.
- Neuroinflammation & Alzheimer's: In Alzheimer's disease, cognitive decline is linked to neuron death triggered by brain inflammation caused by amyloid beta and tau deposits.
- Infiltrating Immune Cells: Massachusetts General Hospital's team created a 3D model revealing that specific immune cells (CT8+ T Cells) worsen neurodegeneration by entering the brain.
- Therapeutic Potential: The study uncovered a pathway (CXCL10-CXCR3) regulating immune cell entry into the brain. Targeting this pathway offers potential for Alzheimer's treatment by reducing neuroinflammation's impact.
A novel 3D human cellular model
Cognitive decline associated with Alzheimer’s disease (AD) develops when neurons begin to die, which can be caused by inappropriate immune responses and excessive inflammation in the brain triggered by amyloid beta deposits and tau tangles, two hallmarks of the disease.
Also, immune cells outside of the brain, particularly T cells, can enter the brain and worsen AD pathology, but studying this process has been difficult.
The work, which builds on previous 3D models of AD developed by the team, is described in Nature Neuroscience.
In the new study, the team used the model to demonstrate that as Alzheimer’s pathology accumulates in the brain, specific types of immune cells called CT8+ T Cells surge into the brain and amplify the destruction caused by neuroinflammation.
The team also identified the molecular mechanisms that drives the infiltration of T cells to the brain and showed that blocking these mechanisms reduced the destructive effects of T cell infiltration.
The findings could lead to new therapies for Alzheimer’s patients that target immune cell infiltration in the brain.
“Enabled by cutting-edge microfluidic technology, this model opens up a window to observe infiltrating peripheral immune cells in action within 3D cell cultures; their interactions with brain cells; and their impact on neuroinflammation and neurodegeneration,” says co-lead author Mehdi Jorfi, PhD, instructor in Neurology at MGH.
“We hope our work contributes to developing a more physiologically relevant human Alzheimer’s disease model in a dish,” adds co–senior author Doo Yeon Kim, PhD, associate professor of Neurology at MGH.
The team’s new model is a 3D human neuroimmune axis model is comprised of stem-cell derived neurons, astrocytes and microglia along with peripheral immune cells.
The model is an extension of previous work done by the research team to create and validate 3D lab models of AD that better replicate the hallmark plaques and tangles of the disease in a three-dimensional environment—much in the same way the disease develops in the brain.
In addition to observing higher levels of T cells in AD brain models, the team identified a pathway between a chemokine (CXCL10) and chemokine receptor (CXCR3) that plays a key role in regulating T cell infiltration.
Blocking this pathway largely prevented T cell infiltration and neurodegeneration in AD cultures.
The findings could help in identifying new therapeutic targets that slow or halt the infiltration of T cells into the brains of Alzheimer’s patients, and potentially reduce the devastating cognitive impacts of the disease.
"This multidisciplinary research approach identified the different behaviors of distinct cell types in this disease context, and we aim to shed light on the underlying mechanisms to identify strategies for intervention that could lead to more effective treatments," said co–lead author Joseph Park, PhD, instructor in Neurology at MGH.
Additional targets may be identified with continued experiments with this model.
“Perhaps, what is most exciting about this study is that we have identified a new drug target on T cells, outside of the brain, which would be more accessible to novel treatments, especially since it has been traditionally difficult to get drugs into the brain,” says senior author Rudolph Tanzi, PhD, director of the Genetics and Aging Research Unit at MGH.
Reference: Jorfi M, Park J, Hall CK, et al. Infiltrating CD8+ T cells exacerbate Alzheimer’s disease pathology in a 3D human neuroimmune axis model. Nat Neurosci. 2023. doi: 10.1038/s41593-023-01415-3
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