Summary: A new study reveals that Alzheimer’s disease involves more than just plaques and tangles; it also stems from disrupted communication between brain cells. Using advanced imaging and computational modeling, scientists mapped how neurons and glial cells interact at the molecular level.
They uncovered the SEMA6D–TREM2 pathway, which helps microglia clear harmful amyloid buildup. This breakthrough highlights cellular crosstalk as a potential therapeutic target, offering a fresh path toward slowing Alzheimer’s progression.
Key Facts
- Crosstalk Discovery: Neurons and glial cells rely on communication pathways that break down in Alzheimer’s.
- New Target Identified: The SEMA6D–TREM2 pathway enhances microglia’s ability to clear amyloid proteins.
- Therapeutic Potential: Cell-to-cell communication may serve as a new molecular target for drug development.
Source: Ohio State University
Research led by The Ohio State University Wexner Medical Center and College of Medicine explores the ways brain cells communicate, revealing fresh insight into the progression of Alzheimer’s disease.
A multidisciplinary team used advanced imaging and computational modeling to analyze the “crosstalk” between neurons and their supporting glial cells in the human brain. This approach highlights the brain’s interconnected cellular network.
“By mapping these cell interactions at the molecular level, we identified key pathways that could be pivotal in both the onset and progression of neurodegeneration,” said study co-author Oscar Harari, PhD, director of the Division of Neurogenetics and director of the Center for Neurobiology of Aging and Resiliency at The Ohio State University Neuroscience Research Institute.
Study findings are published in Science Translational Medicine.
“This insight is critical for developing effective treatments, as ‘cellular crosstalk’ may serve as an attractive molecular target for drug development. Many of these cell-to-cell communication pathways include proteins at the cell membrane, which are often regarded as promising targets for therapeutic intervention,” said Harari, who is also the Helen C. Kurtz Associate Professor of Neurology at Ohio State.
Harari, who joined Ohio State in early 2024, completed the manuscript for the research he started while at the Washington University School of Medicine. He collaborated equally with study co-author Tae-Wan Kim, PhD, associate professor of Pathology and Cell Biology at Columbia University Vagelos College of Physicians and Surgeons in New York.
“Our research shows that Alzheimer’s is not only driven by plaques and tangles, but also by a breakdown in communication between brain cells. By uncovering the SEMA6D–TREM2 crosstalk pathway, we reveal a new way to enhance the amyloid-clearing functions of microglia and potentially slow Alzheimer’s progression,” said Kim.
The study included investigators from The Ohio State University Comprehensive Cancer Center, as well as collaborators from Australia, South Korea, Massachusetts General Hospital, Harvard Medical School, Indiana University School of Medicine, and the Dominantly Inherited Alzheimer Network.
Funding: This research is supported by funding from the National Institute on Aging; National Institute of Neurological Disorders and Stroke; Department of Defense; Chan Zuckerberg Initiative; Alzheimer’s Association; German Center for Neurodegenerative Diseases; Raul Carrea Institute for Neurological Research; Japan Agency for Medical Research and Development; Korea Health Industry Development Institute; Spanish Institute of Health Carlos III; Canadian Institutes of Health Research; Canadian Consortium of Neurodegeneration and Aging; Brain Canada Foundation; Fonds de Recherche du Québec – Santé; Arizona Department of Health Services; Arizona Biomedical Research Commission and Michael J. Fox Foundation for Parkinson’s Research.
About this neurology and Alzheimer’s disease research news
Author: Eileen Scahill
Source: Ohio State University
Contact: Eileen Scahill – Ohio State University
Image: The image is credited to Neuroscience News
Original Research: Closed access.
“Systematic analysis of cellular crosstalk reveals a role for SEMA6D-TREM2 regulating microglial function in Alzheimer’s disease” by Oscar Harari et al. Science Translational Medicine
Abstract
Systematic analysis of cellular crosstalk reveals a role for SEMA6D-TREM2 regulating microglial function in Alzheimer’s disease
Cellular cross-talk, mediated by membrane receptors and their ligands, is crucial for brain homeostasis and can contribute to neurodegenerative diseases such as Alzheimer’s disease (AD).
To find cross-talk dysregulations involved in AD, we reconstructed cross-talk networks from single-nucleus transcriptional profiles of 67 clinically and neuropathologically well-characterized controls and AD brain donors from the Knight Alzheimer Disease Research Center and the Dominantly Inherited Alzheimer Network cohorts.
We predicted a role for TREM2 and additional AD risk genes mediating neuron-microglia cross-talk in AD. We identified a gene network mediating neuron-microglia cross-talk through TREM2 and neuronal SEMA6D, which we predicted is disrupted in late AD stages.
Using spatial transcriptomics on the human brain, we observed that the SEMA6D-TREM2 cross-talk gene network is activated near Aβ plaques and SEMA6D-expressing cells.
Using tissue immunostaining of human brains, we found that SEMA6D colocalizes with Aβ plaques and TREM2-activated microglia. In addition, we found that plaque-proximal SEMA6D abundance decreased with the disease stage, which correlated with a reduction in microglial activation near plaques.
These findings suggest that the loss of SEMA6D signaling impairs microglial activation and Αβ clearance. To validate this hypothesis, we leveraged TREM2 knockout human induced pluripotent stem cell–derived microglia and observed that SEMA6D induces microglial activation and Aβ plaque phagocytosis in a TREM2-dependent manner.
In summary, we demonstrate that characterizing cellular cross-talk networks can yield insights into AD biology, provide additional context to understand AD genetic risk, and find previously unknown therapeutic targets and pathways.
