Summary: New research shows Alzheimer’s disease reflects more than the accumulation of plaques and tangles — it also involves a breakdown in the molecular communication between brain cells. Using advanced imaging, spatial transcriptomics and computational modeling, researchers mapped how neurons and glial cells interact and identified a signaling pathway that influences microglial clearance of amyloid deposits.
The team discovered the SEMA6D–TREM2 signaling axis, which appears to boost microglial responses that help remove harmful amyloid. This finding highlights cellular crosstalk as a promising therapeutic target and points to new strategies for slowing Alzheimer’s progression.
Key Facts
- Crosstalk Discovery: Neurons and glial cells depend on membrane-mediated communication pathways that deteriorate during Alzheimer’s disease.
- New Target Identified: The SEMA6D–TREM2 interaction promotes microglial activation and amyloid clearance.
- Therapeutic Potential: Targeting cell-to-cell signaling may provide new molecular approaches for drug development.
Source: Ohio State University
Research led by The Ohio State University Wexner Medical Center and College of Medicine provides new insight into how brain cells communicate and how those interactions influence Alzheimer’s disease.
A multidisciplinary team combined state-of-the-art imaging techniques with computational network reconstruction to analyze the “crosstalk” between neurons and supporting glial cells in human brain tissue. This integrative approach allowed researchers to chart the brain’s interconnected cellular network and identify signaling pathways altered in Alzheimer’s.
“By mapping these interactions at the molecular level, we pinpointed pathways that could be central to 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.
The full study appears in Science Translational Medicine.
Harari emphasized the translational implications: “Cellular crosstalk may serve as an attractive molecular target for drug development. Many of these communication routes involve membrane proteins, which are accessible to therapeutic strategies.” Harari is also the Helen C. Kurtz Associate Professor of Neurology at Ohio State.
Harari completed this manuscript based on work initiated while he was at Washington University School of Medicine. He collaborated closely with Tae-Wan Kim, PhD, associate professor of Pathology and Cell Biology at Columbia University Vagelos College of Physicians and Surgeons.
“Our data indicate that Alzheimer’s is driven not only by plaques and tangles but also by failures in cell-to-cell signaling,” said Kim. “By characterizing the SEMA6D–TREM2 crosstalk, we reveal a mechanism that can enhance microglial amyloid clearance and potentially slow disease progression.”
The study team included investigators from The Ohio State University Comprehensive Cancer Center and collaborators from institutions in Australia, South Korea, Massachusetts General Hospital, Harvard Medical School, Indiana University School of Medicine, and the Dominantly Inherited Alzheimer Network.
Funding: The research received support 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 the 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., published in Science Translational Medicine.
Abstract
Systematic analysis of cellular crosstalk reveals a role for SEMA6D-TREM2 regulating microglial function in Alzheimer’s disease
Cellular communication mediated by membrane receptors and their ligands is essential for maintaining brain homeostasis, and disruptions in these interactions can contribute to neurodegenerative disorders such as Alzheimer’s disease (AD).
To identify crosstalk dysregulation associated with AD, investigators reconstructed intercellular signaling networks from single-nucleus RNA profiles collected from 67 well-characterized control and AD brain donors from the Knight Alzheimer Disease Research Center and Dominantly Inherited Alzheimer Network cohorts.
Analysis highlighted a role for TREM2 and additional AD risk genes in mediating neuron–microglia interactions. Researchers identified a gene network in which neuronal SEMA6D engages microglial TREM2, a communication axis predicted to be disrupted in advanced stages of AD.
Spatial transcriptomics performed on human brain samples showed activation of the SEMA6D–TREM2 gene network in regions surrounding Aβ plaques and in cells expressing SEMA6D.
Tissue immunostaining of human brain sections revealed colocalization of SEMA6D with amyloid plaques and with microglia that showed TREM2 activation. The abundance of plaque-proximal SEMA6D decreased as disease advanced, a change that correlated with reduced microglial activation near plaques.
These observations suggest that loss of SEMA6D signaling may hinder microglial activation and impair Aβ clearance. To test this, the team used human induced pluripotent stem cell–derived microglia lacking TREM2 and showed that SEMA6D stimulates microglial activation and promotes amyloid phagocytosis in a TREM2-dependent manner.
Overall, this work demonstrates that mapping cellular crosstalk networks in the human brain can illuminate mechanisms of Alzheimer’s biology, clarify how genetic risk factors influence disease processes, and uncover novel therapeutic targets and pathways for future interventions.