A team of scientists has engineered a sophisticated three-dimensional cellular model to scrutinize the complicated interplay between the immune system and neuronal cells in the context of Alzheimer’s disease (AD). This model has elucidated the role of particular immune cells in exacerbating neurological damage in AD, providing new avenues for targeted treatments.
The newly developed model serves as an invaluable tool for understanding AD’s progression and could accelerate the evaluation of emerging therapies.
Cognitive decline associated with Alzheimer’s disease is primarily due to neuronal death. Such neuronal demise often arises from dysfunctional immune responses and increased brain inflammation. These are triggered by the accumulation of amyloid-beta deposits and tau protein aggregates, both characteristic features of the disease.
Furthermore, immune cells such as T cells, which are typically found outside the brain, can infiltrate neural tissues, aggravating the ailment. Researching this specific facet has posed considerable challenges.
The research, spearheaded by experts at Massachusetts General Hospital (MGH), offers a pioneering 3D cellular model that replicates the complex interactions between brain cells and invading immune cells. This project builds upon prior 3D models of AD created by the same group and is documented in the scientific journal Nature Neuroscience.
Utilizing this novel model, the researchers demonstrated that as Alzheimer’s pathology accumulates in the brain, certain immune cells known as CD8+ T cells flood into the brain, exacerbating the damage inflicted by neuroinflammation. The team has also dissected the molecular pathways that facilitate the entry of T cells into the brain and have shown that obstructing these pathways mitigates the harmful effects of T cell invasion.
The research findings have the potential to pave the way for innovative Alzheimer’s treatments that specifically focus on inhibiting immune cell infiltration into the brain.
The model, empowered by state-of-the-art microfluidic technology, enables direct observation of these infiltrating peripheral immune cells within three-dimensional cellular cultures. It sheds light on their interactions with neuronal cells and their subsequent influence on neuroinflammation and neurodegeneration, according to Mehdi Jorfi, Ph.D., a co-lead author and instructor in Neurology at MGH.
Doo Yeon Kim, Ph.D., associate professor of Neurology at MGH and co-senior author, further states that the aim of this groundbreaking work is to contribute to the creation of a more physiologically pertinent human model of Alzheimer’s disease.
The model employs a 3D human neuroimmune axis, composed of stem-cell-derived neurons, astrocytes, and microglia in conjunction with peripheral immune cells. This design extends prior achievements by the research team in creating more accurate 3D lab models of Alzheimer’s disease.
Moreover, the team identified a key regulatory pathway involving a specific chemokine (CXCL10) and chemokine receptor (CXCR3), which controls T cell infiltration. Inhibition of this pathway substantially curtailed T-cell entry and subsequent neural degeneration in Alzheimer’s models.
These discoveries may contribute to the identification of new therapeutic strategies to mitigate or halt the deleterious entry of T cells into the brains of Alzheimer’s patients, thereby potentially alleviating the disease’s severe cognitive repercussions.
Joseph Park, Ph.D., another co-lead author and instructor in Neurology at MGH, noted that the multidisciplinary research approach discerned various cellular behaviors in this disease milieu, with the objective of elucidating the underlying mechanisms for future treatment interventions.
Continued research with this model may unveil additional targets for therapeutic interventions. Senior author Rudolph Tanzi, Ph.D., director of the Genetics and Aging Research Unit at MGH, emphasized that this study’s most promising aspect is the identification of a novel drug target on T cells, making it more amenable to new treatments, especially considering the traditional challenges of drug delivery to the brain.
This endeavor was financially supported by the Cure Alzheimer’s Fund and the JPB Foundation.
Reference: “Infiltrating CD8+ T cells exacerbate Alzheimer’s disease pathology in a 3D human neuroimmune axis model” by Mehdi Jorfi, Joseph Park, et al., published in Nature Neuroscience on 24 August 2023.
DOI: 10.1038/s41593-023-01415-3
Table of Contents
Frequently Asked Questions (FAQs) about 3D Cellular Model in Alzheimer’s Research
What is the primary focus of the research led by Massachusetts General Hospital?
The primary focus of the research is to understand the complex interactions between immune cells and brain cells in Alzheimer’s Disease (AD) using a sophisticated 3D cellular model. This model aims to elucidate how specific immune cells, particularly CD8+ T cells, contribute to brain damage in AD.
Who are the primary contributors to this study?
The primary contributors to this study are experts at Massachusetts General Hospital (MGH). Co-lead authors include Mehdi Jorfi, Ph.D., and Joseph Park, Ph.D., both instructors in Neurology at MGH. The senior author is Rudolph Tanzi, Ph.D., director of the Genetics and Aging Research Unit at MGH.
What does the 3D cellular model help to achieve?
The 3D cellular model serves as a valuable tool for studying the intricate interactions between immune cells and brain cells in Alzheimer’s disease. It offers insights into the disease’s progression and can accelerate the evaluation of new treatments.
How does Alzheimer’s disease cause cognitive decline, according to this research?
According to the study, cognitive decline in Alzheimer’s disease occurs primarily due to the death of neurons. This neuronal death is often instigated by dysfunctional immune reactions and heightened inflammation in the brain, which are triggered by the accumulation of amyloid-beta deposits and tau protein aggregates.
What are the key findings related to immune cells in this research?
The key findings reveal that specific types of immune cells called CD8+ T cells infiltrate the brain and exacerbate the damage caused by neuroinflammation in Alzheimer’s disease. The research also identified the molecular mechanisms that facilitate this infiltration and showed that blocking these mechanisms can mitigate the damaging effects.
What potential therapeutic avenues does this research open up?
The study offers new avenues for targeted therapies in Alzheimer’s disease, particularly focusing on inhibiting the infiltration of immune cells like CD8+ T cells into the brain. It highlights molecular pathways that could serve as targets for new treatments.
Are there any novel drug targets identified?
Yes, the study identifies a new drug target on T cells, making it more amenable to treatments. This is especially promising given the traditional challenges associated with delivering drugs to the brain.
Who funded this research?
The research was financially supported by the Cure Alzheimer’s Fund and the JPB Foundation.
Where was this research published?
The research was published in the scientific journal Nature Neuroscience on 24 August 2023. The DOI for the article is 10.1038/s41593-023-01415-3.
More about 3D Cellular Model in Alzheimer’s Research
- Nature Neuroscience Journal
- Massachusetts General Hospital Neurology Department
- Cure Alzheimer’s Fund
- JPB Foundation
- Alzheimer’s Disease Information
- Microfluidic Technology in Neuroscience
- Inflammation and Alzheimer’s Disease
- Molecular Mechanisms in Alzheimer’s Disease
- Stem Cells and Neurological Diseases
7 comments
Wow, this is pretty huge for Alzheimer’s research. Finally some real advancements that can actually help in finding new treatments.
This is all super techy and a bit over my head, but if it means we’re getting closer to beating Alzheimer’s, I’m all for it. Kudos to the researchers.
Blocking the pathway to prevent T-cell infiltration, thats sounds promising. But also, its kinda scary how our own immune system can turn against us like that.
Did anyone catch that they’ve actually identified a new drug target? that’s usually a long and complicated process. Big win here!
My grandma had Alzheimer’s and its a horrible disease. Anything that gives us hope for a cure is more than welcome. Thank u scientists.
the 3D model sounds like a game changer. Imaging actually seeing how immune cells mess with our brain. it’s mind-blowing and terrifying at the same time.
I’m glad MGH is making strides here, but how long til we see these findings turn into real-world solutions? People are suffering now.