Novel Alzheimer risk genes determine the microglia response to amyloid-β but not to TAU pathology
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Abstract
Polygenic risk scores have identified that genetic variants without genome‐wide significance still add to the genetic risk of developing Alzheimer's disease (AD). Whether and how subthreshold risk loci translate into relevant disease pathways is unknown. We investigate here the involvement of AD risk variants in the transcriptional responses of two mouse models: APPswe/PS1 L166P and Thy‐TAU22. A unique gene expression module, highly enriched for AD risk genes, is specifically responsive to Aβ but not TAU pathology. We identify in this module 7 established AD risk genes ( APOE , CLU , INPP5D , CD33, PLCG2 , SPI1, and FCER1G ) and 11 AD GWAS genes below the genome‐wide significance threshold ( GPC2, TREML2, SYK, GRN, SLC2A5, SAMSN1, PYDC1, HEXB, RRBP1, LYN, and BLNK), that become significantly upregulated when exposed to Aβ. Single microglia sequencing confirms that Aβ, not TAU, pathology induces marked transcriptional changes in microglia, including increased proportions of activated microglia. We conclude that genetic risk of AD functionally translates into different microglia pathway responses to Aβ pathology, placing AD genetic risk downstream of the amyloid pathway but upstream of TAU pathology.
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Sierskma et al. identified 18 genes that both overlapped with AD GWAS datasets and were maintained between young and old APP transgenic mice.
“Sierskma et al. identified 18 genes that both overlapped with AD GWAS datasets and were maintained between young and old APP transgenic mice, which were predominantly expressed by microglia and appear to be regulated by Spi150.”
From Modest changes in Spi1 dosage reveal the potential for altered microglial function as seen in Alzheimer’s disease (2021) · cites this paper as [50]
The Results section on prioritization identifies 18 genes at the intersection of AD GWAS genes, the APPtg-Blue module, and genes differentially expressed in the APPtg age-by-genotype comparison. Figure 4 and the accompanying Results support their microglial expression and possible regulation by Spi1. The paper does not say their expression was maintained between young and old APP transgenic mice; differential expression with age was a selection criterion. Page numbers are not available in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThose 18 genes were predominantly expressed by microglia and appear to be regulated by Spi1.
“Sierskma et al. identified 18 genes that both overlapped with AD GWAS datasets and were maintained between young and old APP transgenic mice, which were predominantly expressed by microglia and appear to be regulated by Spi150.”
From Modest changes in Spi1 dosage reveal the potential for altered microglial function as seen in Alzheimer’s disease (2021) · cites this paper as [50]
Recent scRNA-seq studies identified marked transcriptional changes in microglia in response to Aβ.
“Furthermore, recent scRNA-seq studies identified marked transcriptional changes in microglia in response to Aβ (52).”
From Deletion of <i>Abi3</i> gene locus exacerbates neuropathological features of Alzheimer’s disease in a mouse model of Aβ amyloidosis (2021) · cites this paper as [52]
Several studies have shown that transcriptional signatures can be used to investigate Aβ accumulation, region-specific expression of tau, and activated immune response.
“Several studies have shown that this hypothesis-generating, unbiased readout can be used to investigate Aβ accumulation (Sierksma et al., 2020), region-specific expression of tau (Castanho et al., 2020), and activated immune response (Kang et al., 2018).”
From Network analysis identifies strain-dependent response to tau and tau seeding-associated genes (2023) · cites this paper as Sierksma et al., 2020
Single microglia sequencing of two different mouse models of AD, one displaying either Aβ or tau pathology, confirmed expression of AD risk genes, including PLCG2, and confirmed that more microglia adopt an activated phenotype when facing Aβ than tau pathology.
“Single microglia sequencing of two different mouse models of AD, one displaying either Aβ or tau pathology, further confirmed the expression of AD risk genes, including PLCG2 gene, and also confirmed that more microglia adopt an activated phenotype when facing Aβ than tau pathology (166).”
From The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration (2021) · cites this paper as [166]
Computational models place TREM2 and other effectors in the pathway - including Syk and BLNK - in a module associated with microglia responses to Aβ.
“Computational models place TREM2 and other effectors in the pathway – including Syk and BLNK – in a module associated with microglia responses to Aβ [91].”
From TREM2/PLCγ2 signalling in immune cells: function, structural insight, and potential therapeutic modulation (2021) · cites this paper as [91]
The 'APPtg-greenyellow' module is an oligodendroglial response in the amyloid- but not the tau-model.
“which is an oligodendroglial response in the amyloid- but not the tau-model.”
From Spatial Transcriptomics and In Situ Sequencing to Study Alzheimer’s Disease (2020) · cites this paper as Sierksma et al., 2020
The 'APPtg blue' module is enriched with AD risk genes and is a microglial response to amyloid rather than tau pathology.
“which is enriched with AD risk genes and is a microglial response to amyloid rather than tau pathology.”
From Spatial Transcriptomics and In Situ Sequencing to Study Alzheimer’s Disease (2020) · cites this paper as Sierksma et al., 2020
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“1 3 associated with both pathological proteins, a 3–4-fold greater number of genes were uniquely differentially expressed with amyloid-beta relative to pTau, mirroring observations with microglia in preclinical transgenic models overexpressing the two proteins [55].”
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“Human genetic data were further corroborated by using well-studied animal models of AD (165, 166).”
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BackgroundRedefining Microglial Identity in Health and Disease at Single-Cell Resolution
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Cuní‐López, C., Stewart, R., Oikari, L. E., Nguyen, T. H., Roberts, T. L., Sun, Y., Guo, C. C., Lupton, M. K., White, A. R., & Quek, H. (2024) · Journal of Neuroinflammation · doi:10.1186/s12974-024-03037-3 · Cited by 28 · see citing works
Altered Metabolism and DAM-signatures in Female Brains and Microglia with Aging
Cleland, N. R. W., Potter, G. J., Buck, C., Quang, D., Oldham, D., Neal, M., Saviola, A., Niemeyer, C. S., Dobrinskikh, E., & Bruce, K. D. (2024) · Brain Research · doi:10.1016/j.brainres.2024.148772 · Cited by 26 · see citing works
How the gut microbiota impacts neurodegenerative diseases by modulating CNS immune cells
Schaible, P., Henschel, J., & Erny, D. (2025) · Journal of Neuroinflammation · doi:10.1186/s12974-025-03371-0 · Cited by 31 · see citing works
Immune dysfunction in Alzheimer disease
Butovsky, O., Rosenzweig, N., Kleemann, K. L., Jorfi, M., Kuchroo, V. K., Tanzi, R. E., & Weiner, H. L. (2025) · Nature reviews. Neuroscience · doi:10.1038/s41583-025-00997-0 · Cited by 34 · see citing works
Zhang, Z., Wu, H., Peng, Q., Xie, Z., Chen, F., Ma, Y., Zhang, Y., Zhou, Y. C., Yang, J., Cheng Ann, C. H. E. N., et al. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.730300 · Cited by 26 · see citing works
Wu, D., Bi, X., & Chow, H. (2024) · Journal of Neuroinflammation · doi:10.1186/s12974-023-02987-4 · Cited by 27 · see citing works
Moon, H.-J., Haroutunian, V., & Zhao, L. (2022) · Neurobiology of Disease · doi:10.1016/j.nbd.2022.105631 · Cited by 25 · see citing works
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S100A8 ‐enriched microglia populate the brain of tau‐seeded and accelerated aging mice
Gruel, R., Bijnens, B., Daele, J. V. D., Thys, S., Willems, R., Wuyts, D., Dam, D. V., Verstraelen, P., Verboven, R., Roels, J., et al. (2024) · Aging Cell · doi:10.1111/acel.14120 · Cited by 23 · see citing works
Self-citationHemonnot-Girard, A.-L., Meersseman, C., Pastore, M., Garcia, V., Linck, N., Rey, C., Chebbi, A., Jeanneteau, F., Ginsberg, S. D., Lachuer, J., et al. (2022) · Journal of Neuroinflammation · doi:10.1186/s12974-022-02581-0 · Cited by 24 · see citing works
- Authors
- Sierksma, A., Lu, A., Mancuso, R., Fattorelli, N., Thrupp, N., Salta, E., Zoco, J., Blum, D., Buée, L., De Strooper, B., & Fiers, M.
- Affiliations
- VIB-KU Leuven Center for Brain & Disease Research (BE)
- Inserm (FR)
- Corresponding author
- Fiers, Mark
- ORCID
- Venue
- EMBO Molecular Medicine
- Published
- 2020-01-17
- Volume
- 12
- Issue
- 3
- Pages
- e10606-e10606
- ISSN
- 1757-4676 (ISSN-L)
- 1757-4684
- PMC
- PMC7059012
- OpenAlex
- W3000035810
- Cited by
- 291
- References
- 74
- Citations by year
- 2026: 21 · 2025: 43 · 2024: 37 · 2023: 48 · 2022: 58 · 2021: 54 · 2020: 28 · 2019: 1 · 2018: 1
- FWCI
- 28.26
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- EMBO Molecular Medicine (publishedVersion, other-oa)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Lirias (KU Leuven) (acceptedVersion)
- Lirias (submittedVersion, other-oa)
- Lirias (KU Leuven) (submittedVersion, other-oa)
- HAL (submittedVersion, other-oa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- Leuven Universitair Fonds
- Alzheimer Research Foundation (P16017)
- Fonds voor Wetenschappelijk Onderzoek (1139520N, 12A5316N, G0C9219N)
- Alzheimer's Association (AARF‐16‐442853)
- KU Leuven
- Vlaams Instituut voor Biotechnologie
- Vlaamse Overheid
- Vlaams Initiatief voor Netwerken voor Dementie Onderzoek
- Geneeskundige Stichting Koningin Elisabeth
- Bax‐Vanluffelen Chair for Alzheimer's Disease
- Agence National Recherche (ANR‐16‐COEN‐0007)
- UK Research and Innovation|MRC|Medical Research Foundation
- Alzheimer Society
- Alzheimer Research UK
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- Alzheimer's disease, Alzheimer's disease risk genes, microglia, amyloid-beta, tau pathology, polygenic risk score, single-cell RNA sequencing, microglial activation, apolipoprotein E, clusterin, CD33, PLCγ2, PU.1, FCER1G, Syk, GPC2
- MeSH terms
- Alzheimer Disease, Animals, Disease Models, Animal, Hippocampus, Male, Mice, Transgenic, Amyloid beta-Peptides, tau Proteins, Microglia, Mice, Gene Regulatory Networks
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