Expression of GPR34 in microglia remains stable in human Alzheimer's disease.

Overview

1. Institute of Anatomy, Faculty of Medicine, Leipzig University, Liebigstraße 13, 04103 Leipzig, Germany
2. Paul Flechsig Institute of Neuropathology, University Hospital Leipzig, Leipzig, Germany
3. Rudolf Schönheimer Institute of Biochemistry, Faculty of Medicine, Leipzig University, Leipzig, Germany
4. Department of Biochemistry, School of Medicine, University of Global Health Equity (UGHE), Kigali, Rwanda
5. LeiCeM - Leipzig Center of Metabolism, Leipzig University, Leipzig, Germany

Abstract

Microglia are the resident immune cells of the human central nervous system and play key roles in development, homeostasis, and disease. These functions are mediated by a broad repertoire of cell-surface receptors, including G protein-coupled receptors such as the ADP receptor P2Y12 and GPR34, a receptor for lysophosphatidylserine. While GPR34 deficiency has been linked to impaired microglial phagocytosis, its regulation in relation to amyloid-β (Aβ) and tau pathology in Alzheimer’s disease (AD) remains unclear. We performed a quantitative analysis of microglial density, morphology, and GPR34 expression in the medial temporal lobe cortex (MTLC) of elderly human body and tissue donors across the AD spectrum. Using fluorescence in situ hybridization and immunolabeling, we analyzed 187,670 microglial cells and correlated microglial parameters with the severity and spatial proximity of Aβ plaques and tau inclusions. In parallel, we analyzed human single-nucleus RNA sequencing data from 236,002 cells to assess GPR34 expression across microglial subtypes, brain regions, and neuropathological stages. Microglial density and overall morphology in the MTLC were largely preserved, independent of local Aβ or hyperphosphorylated tau burdens. Apart from a moderate shortening of microglial processes in the immediate vicinity of Aβ plaques, no consistent pathology-associated morphological changes were detected. GPR34 expression showed pronounced cell-to-cell variability and differed across microglial subtypes and brain regions, but neither expression intensity nor the proportion of GPR34-positive microglia correlated consistently with Braak stage or Thal phase. These findings suggest that GPR34 regulation in human microglia is highly context-dependent and shaped by regional and cellular heterogeneity rather than AD-associated pathology alone.

Supplementary Information: The online version contains supplementary material available at 10.1007/s00401-026-03035-0.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data availability

All data and materials generated in this study, including microscopy images and analytical outputs, are available from the corresponding author upon reasonable request. The snRNA-seq data were obtained from the Seattle Alzheimer's Disease Brain Cell Atlas (SEA-AD) consortium and are publicly available through the Allen Institute Brain Map data portal (https://brain-map.org/consortia/sea-ad/our-data). The microglia and immune cell dataset is accessible through the SEA-AD data repository at https://sea-ad-single-cell-profiling.s3.amazonaws.com/index.html#Microglia-and-Immune-for-AAIC/. Custom analysis scripts used for data processing and visualization are available from the corresponding author upon reasonable request.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Version 2, 28 September 2026

• Publisher: n/a → Springer Science+Business Media

Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 10 authors, 5 keywords, 12 MeSH terms, 1 funder, 129 references.

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This paper

Seiffer, S., Rotter, J., Brendler, J., Ricken, A., Detzer, Z., Braune, M., Schöneberg, T., Schulz, A., Winter, K., & Bechmann, I. (2026). Expression of GPR34 in microglia remains stable in human Alzheimer's disease. Acta neuropathologica, 151(1), 66. https://doi.org/10.1007/s00401-026-03035-0

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