3D Model Reveals T Cell Role in Alzheimer’s Progression

Summary: Researchers developed a 3D cellular model to study the interactions between brain cells and immune cells in Alzheimer’s disease. Based on advanced microfluidic technology, this new model demonstrates that specific immune cells, CT8+ T Cells, amplify Alzheimer’s pathology when they infiltrate the brain.

The team pinpointed a pathway regulating T cell infiltration and showed that blocking this pathway can prevent neurodegeneration in Alzheimer’s cultures. Their discoveries pave the way for potential new treatments targeting immune cell infiltration.

Key Facts:

  1. The 3D human neuroimmune axis model, an extension of the team’s previous models, accurately mimics the interactions between Alzheimer’s-associated brain cells and immune cells.
  2. The research identified a chemokine pathway (CXCL10-CXCR3) crucial for T cell infiltration in Alzheimer’s brains, which when blocked can deter neurodegeneration.
  3. This research, backed by advanced microfluidic technology, presents a more physiologically relevant “Alzheimer’s disease in a dish”, offering insights for developing potential treatments.

Source: Mass General

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.

Now, a team led by researchers at Massachusetts General Hospital (MGH) has engineered a novel 3D human cellular model that mimics the intricate interactions between brain cells and these immune invaders.

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.

“his 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.

Additional co-authors include Clare K. Hall, Chih-Chung Jerry Lin, Meng Chen, Djuna von Maydell, Jane M. Kruskop, Byunghoon Kang, Younjung Choi, Dmitry Prokopenko, and Daniel Irimia.

Funding: This work was supported by the Cure Alzheimer’s Fund and the JPB Foundation. 

About this Alzheimer’s disease research news

Author: Brandon Chase
Source: Mass General
Contact: Brandon Chase – Mass General
Image: The image is credited to Neuroscience News

Original Research: Closed access.
Infiltrating CD8+ T cells exacerbate Alzheimer’s disease pathology in a 3D human neuroimmune axis model” by Mehdi Jorfi et al. Nature Neuroscience


Infiltrating CD8+ T cells exacerbate Alzheimer’s disease pathology in a 3D human neuroimmune axis model

Brain infiltration of peripheral immune cells and their interactions with brain-resident cells may contribute to Alzheimer’s disease (AD) pathology.

To examine these interactions, in the present study we developed a three-dimensional human neuroimmune axis model comprising stem cell-derived neurons, astrocytes and microglia, together with peripheral immune cells.

We observed an increase in the number of T cells (but not B cells) and monocytes selectively infiltrating into AD relative to control cultures. Infiltration of CD8+ T cells into AD cultures led to increased microglial activation, neuroinflammation and neurodegeneration.

Using single-cell RNA-sequencing, we identified that infiltration of T cells into AD cultures led to induction of interferon-γ and neuroinflammatory pathways in glial cells.

We found key roles for the C-X-C motif chemokine ligand 10 (CXCL10) and its receptor, CXCR3, in regulating T cell infiltration and neuronal damage in AD cultures.

This human neuroimmune axis model is a useful tool to study the effects of peripheral immune cells in brain disease.

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