A proteogenomic tool uncovers protein markers for human microglial states

Haage, V.; Bautista, A. R.; Tuddenham, J. F.; Marshe, V.; Chiu, R.; Liu, Y.; Lama, T.; Kelly, S. S.; Parghi, N. A.; Park, J.; Buonfiglioli, A.; Furnari, J. L.; Haq, I.; Pearse, R.; Patel, R.; Terzioglu, G.; Touil, H.; Zeng, L.; Noble, J.; Sarkis, R. A.; Shneider, N. A.; de Witte, L.; Schneider, J. A.; Teich, A.; Young-Pearse, T. L.; Riley, C.; Bennett, D. A.; Canoll, P.; Bruce, J. N.; Howden, A. J.; Lloyd, A. F.; De Strooper, B. F.; Sher, F.; Sproul, A. A.; Olah, M.; Taga, M.; Zhang, Y.; Caisheng, L.; Fujita, M.; Petyuk, V. A.; De Jager, P. A.

doi:10.1101/2025.03.31.646212

Home/Archive/bioRxiv

bioRxiv · 10.1101/2025.03.31.646212

A proteogenomic tool uncovers protein markers for human microglial states

View original source ↗Export metadata ↓

Abstract

Human microglial heterogeneity has been largely described using transcriptomic data. Here, we introduce a microglial proteomic data resource and a Cellular Indexing of Transcriptomes and Epitopes by Sequencing panel enhanced with antibodies targeting 17 microglial cell surface proteins (mCITE-Seq). We evaluated mCITE-Seq on HMC3 microglia-like cells, induced-pluripotent stem cell-derived microglia (iMG), and freshly isolated primary human microglia. We identified novel protein microglial markers such as CD51 and relate expression of 101 cell surface proteins to transcriptional programs. This results in the identification and validation of three protein marker combinations with which to purify microglia enriched with each of 23 transcriptional programs; for example, CD49D, HLA-DR and CD32 enrich for GPNMBhigh ("disease associated") microglia. Further, we identify and validate proteins - SIRPA, PDPN and CD162 - that differentiate microglia from infiltrating macrophages. The mCITE-Seq panel enables the transition from RNA-based classification and facilitates the functional characterization and harmonization of model systems.

Explore related subjects

neuroscience Preprint

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

Haage, V., Bautista, A. R., Tuddenham, J. F., Marshe, V., Chiu, R., Liu, Y., Lama, T., Kelly, S. S., Parghi, N. A., Park, J., Buonfiglioli, A., Furnari, J. L., Haq, I., Pearse, R., Patel, R., Terzioglu, G., Touil, H., Zeng, L., Noble, J., Sarkis, R. A., Shneider, N. A., de Witte, L., Schneider, J. A., Teich, A., Young-Pearse, T. L., Riley, C., Bennett, D. A., Canoll, P., Bruce, J. N., Howden, A. J., Lloyd, A. F., De Strooper, B. F., Sher, F., Sproul, A. A., Olah, M., Taga, M., Zhang, Y., Caisheng, L., Fujita, M., Petyuk, V. A., De Jager, P. A.. 2025-04-04. A proteogenomic tool uncovers protein markers for human microglial states. https://doi.org/10.1101/2025.03.31.646212

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Rab10 and Arhgef7 interact to promote axon extension by linking vesicle supply and exocytosis

The formation of functional neural circuits begins with the extension of a single axon by immature neurons. Axon elongation requires an expansion of the plasma membrane that depends on the polarization of vesicle trafficking and exocytosis. It is not completely understood how the increased transport of vesicles into the growing axon is linked to their subsequent insertion into the plasma membrane. An analysis of early stages of neuronal differentiation indicates that an asymmetry in neurite length precedes axon specification and the accumulation of PPVs in the nascent axon. We show that increasing the transport of vesicles in unpolarized neurons is sufficient to promote the extension of additional axons. This effect indicates that an increased supply of vesicles stimulates their subsequent insertion into the membrane to allow neurite growth. The link between vesicle transport and exocytosis is mediated by the interaction of Rab10 with Arhgef7. Rab10 stimulates Arhgef7 activity on PPVs as a GEF for Cdc42b to promote axon extension through exocyst-dependent exocytosis, suggesting that their interaction links the increased supply of PPVs to their exocytosis.

neuroscience↗

bioRxiv2026

Subcellular Spatial Profiling Unveils Links Between Neuritic Plaques with Selective Tau Vulnerability in Alzheimer's Disease

Alzheimer's disease (AD) features widespread extracellular amyloid-{beta} plaques but selective intraneuronal tau accumulation in cortical layers II/III and V, while layer IV remains relatively resistant. Here, we combined subcellular spatial transcriptomics with co-registered A{beta} and pTau immunohistochemistry to determine why neurons exposed to comparable plaque-associated pathology differ in somatic pTau accumulation. Plaque-associated neuritic stress occurred similarly across layers, but layer IV neurons showed attenuated pTau accumulation and reduced somatic expression of a shared neurite-soma stress program involving DCTN1, CALM3, NORAD, and PIN1. Trajectory analysis within layers identified tau-vulnerable and resistant neuronal states implicating calcium signaling, retrograde transport, and lysosomal function. Notably, astrocytic APOE-neuronal LRP1 co-expression increased significantly along the pTau-vulnerable trajectory, and APOE {epsilon}4 was associated with stronger coupling of local plaque pathology to pTau-associated molecular programs. These findings reveal neuronal programs and neuron-glia interactions underlying selective tau vulnerability and resistance in AD, highlighting potential tau-targeting therapeutics.

neuroscience↗

bioRxiv2026

Widespread oscillatory suppression in autism persists in the absence of psychotropic medication.

Purpose: Investigate the neural oscillatory activity associated with autism spectrum disorder (ASD) using electroencephalographic (EEG) recordings in children and adolescents. Compare the corresponding oscillatory power between ASD patients taking psychotropic medication with a drug-naive group. Methods: ASD diagnosis was done using DSM-IV and CARS (Childhood Autism Rating Scale). EEG recordings employed 22 scalp electrodes (10/20 system). ASD vs. neurotypical groups were matched for sex and age (5 females; average age: ~10 years old). We analyzed the resting state (eyes open) EEG power spectrum during ~2-minute recordings. The multitaper FFT method was used to estimate spectral power for the delta, theta, alpha, beta and gamma frequency bands. We pooled together data from several electrodes to compute comprehensive power spectra and assess the oscillatory behavior of macro brain regions. Results: We observed widespread (~4Hz - 20Hz) oscillatory suppression comprising the theta, alpha and beta frequency bands. The most widespread and robust ASD-associated power suppression was in the high theta and alpha bands. Delta and gamma bands showed no significant power change for any of the brain regions studied. Results from a subgroup of patients (N = 9) who never used psychotropics confirmed these findings, indicating that they are not an artifact of medication. Conclusion: Suppression in theta, alpha and beta oscillations may offer insights into the neurophysiological underpinnings of autism and could be used as an accessible and comprehensive tool in ASD diagnosis, regardless of the patients being or not on medication.

neuroscience↗