Neuron-derived SPP1 instructs microglia to limit degeneration.

Overview

1. Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USA
2. Schepens Eye Research Institute, Massachusetts Eye and Ear, Boston, MA 02114, USA

Abstract

Neurons actively shape immune responses that maintain central nervous system integrity. We identify SPP1 (secreted phosphoprotein 1) as a neuron-derived signal that reprograms microglia into a neuroprotective, homeostatic state after injury and during neurodegeneration. In mouse models of glaucoma and optic nerve damage, neuronal SPP1 enhances microglial autophagy, debris clearance, and anti-inflammatory activity, preserving neuronal survival and visual function. SPP1 is elevated in neurons of human and primate glaucomatous retinas, where SPP1+ cells show increased resilience. In Alzheimer’s disease brain, neuronal SPP1 correlates with neuronal survival, while microglia around Aβ plaques display defective autophagy. In human iPSC co-cultures, SPP1 enhances microglial Aβ clearance and prevents neurodegeneration. Thus, SPP1 defines a protective neuron–microglia axis in glaucoma and possibly other neurodegenerative diseases.

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

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Data

Datasets cited

• doi:10.7910/dvn/2gcscm, at the source; found in “Data, code, and materials availability:”
• geo:GSE304931, at NCBI GEO; found in the text, “RNA-seq analysis”

Data, code, and materials availability

All data and code needed to evaluate and reproduce the results in the paper are present in the paper and/or the Supplementary Materials. This study did not generate new materials. The code for RGC counting and microglial morphology analysis is available on Dataverse and can be accessed via this unique DOI: https://doi.org/10.7910/DVN/2GCSCM. The code for RNA-seq analysis is available on Dataverse and can be accessed via this unique DOI: https://doi.org/10.7910/DVN/WJ0MJI. The RNA-sequencing data have been deposited in the NCBI Gene Expression Omnibus (GEO) under accession code GEO: GSE304931 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE304931).

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

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Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 2 authors, 11 MeSH terms, 1 funder, 107 references.

Cite

This paper

Li, S., & Jakobs, T. C. (2026). Neuron-derived SPP1 instructs microglia to limit degeneration. Science advances, 12(35), eaee4940. https://doi.org/10.1126/sciadv.aee4940

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