The adaptive immune system restrains Alzheimer’s disease pathogenesis by modulating microglial function
Open accessAbstract
The innate immune system is strongly implicated in the pathogenesis of Alzheimer's disease (AD). In contrast, the role of adaptive immunity in AD remains largely unknown. However, numerous clinical trials are testing vaccination strategies for AD, suggesting that T and B cells play a pivotal role in this disease. To test the hypothesis that adaptive immunity influences AD pathogenesis, we generated an immune-deficient AD mouse model that lacks T, B, and natural killer (NK) cells. The resulting "Rag-5xfAD" mice exhibit a greater than twofold increase in β-amyloid (Aβ) pathology. Gene expression analysis of the brain implicates altered innate and adaptive immune pathways, including changes in cytokine/chemokine signaling and decreased Ig-mediated processes. Neuroinflammation is also greatly exacerbated in Rag-5xfAD mice as indicated by a shift in microglial phenotype, increased cytokine production, and reduced phagocytic capacity. In contrast, immune-intact 5xfAD mice exhibit elevated levels of nonamyloid reactive IgGs in association with microglia, and treatment of Rag-5xfAD mice or microglial cells with preimmune IgG enhances Aβ clearance. Last, we performed bone marrow transplantation studies in Rag-5xfAD mice, revealing that replacement of these missing adaptive immune populations can dramatically reduce AD pathology. Taken together, these data strongly suggest that adaptive immune cell populations play an important role in restraining AD pathology. In contrast, depletion of B cells and their appropriate activation by T cells leads to a loss of adaptive-innate immunity cross talk and accelerated disease progression.
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Genetic and antibody-based B cell inactivation strategies in AD mouse models have yielded conflicting results.
“researchers have employed both genetic and antibody-based B cell inactivation strategies, though these approaches have yielded conflicting results.”
From Is there a role for B cells in Alzheimer's disease? (2026) · cites this paper as [109]
In “Generation of an Immune-Deficient AD Mouse Model” (page unavailable), the paper describes a genetic knockout that removes B cells along with T and NK cells, and reports increased amyloid pathology. Our copy does not describe antibody-based B-cell inactivation or conflicting results between the two strategies; its antibody experiments concern IgG and amyloid clearance. (LLM, conf=0.86)
Experimental — accuracy not yet measuredB cells and their antibodies have a protective role in the 5xFAD model.
“suggesting a protective role for B cells and their antibodies in this model [109].”
From Is there a role for B cells in Alzheimer's disease? (2026) · cites this paper as [109]
Rag2-/-Il2rγ-/-5xFAD mice had increased amyloid pathogenesis and exacerbated neuroinflammation.
“These Rag2 /-Il2r γ /-5xFAD mice had increased amyloid pathogenesis, and exacerbated neuroinflammation [109].”
From Is there a role for B cells in Alzheimer's disease? (2026) · cites this paper as [109]
Restoring IgG as principal secretory protein from B cells, either through intracerebral injection or bone marrow transplantation, mitigated Aβ pathology.
“restoring IgG as prin cipal secretory protein from B cells, either through intracerebral injec tion or bone marrow transplantation, mitigated A β pathology”
From Is there a role for B cells in Alzheimer's disease? (2026) · cites this paper as [109]
Depletion of T cells, B cells, and natural killer (NK) cells contributes to an increase in Aβ deposition.
“It has previously been shown that the depletion of T cells, B cells, and natural killer (NK) cells contributes to an increase in Aβ deposition [4–6].”
From Control of the temporal development of Alzheimer’s disease pathology by the MR1/MAIT cell axis (2023) · cites this paper as [4]
Rag5xfAD mice show robust beta-amyloid pathology and permit xenotransplantation of human cells.
“Rag5xfAD mice display robust beta-amyloid pathology and allow for xenotransplantation of human cells.”
From iPSC-derived human microglia-like cells to study neurological diseases (2017) · cites this paper as Marsh et al., 2016
iMGLs transplanted into the hippocampi of xenotransplantation-compatible AD mice engraft and migrate along white matter tracts, similar to microglia in development.
“Transplanted iMGLs engraft and migrate along white matter tracts, similar to microglia in development (Figure 7M).”
From iPSC-derived human microglia-like cells to study neurological diseases (2017) · cites this paper as Marsh et al., 2016
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- Authors
- Marsh, S. E., Abud, E. M., Lakatos, A., Karimzadeh, A., Yeung, S. T., Davtyan, H., Fote, G. M., Lau, L., Weinger, J. G., Lane, T. E., Inlay, M. A., Poon, W. W., & Blurton-Jones, M.
- Affiliations
- University of California, Irvine (US)
- Institute for Molecular Medicine (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2016-02-16
- Volume
- 113
- Issue
- 9
- Pages
- E1316-25
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC4780638
- OpenAlex
- W2275744255
- Cited by
- 411
- References
- 65
- Citations by year
- 2026: 27 · 2025: 32 · 2024: 51 · 2023: 48 · 2022: 54 · 2021: 42 · 2020: 37 · 2019: 43 · 2018: 31 · 2017: 30 · 2016: 16
- FWCI
- 21.76
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- HHS | NIH | National Institute on Aging (RF1 AG048099, P50 AG016573, T32 AG00096)
- Alzheimer's Association (BFG-14-317000)
- HHS | NIH | National Institute of Neurological Disorders and Stroke (T32 NS082174)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Keywords
- Alzheimer's disease, adaptive immunity, microglia, T cells, B cells, natural killer cells, amyloid-beta, neuroinflammation, bone marrow transplantation, amyloid clearance, microglial phagocytosis
- MeSH terms
- Adaptation, Physiological, Alzheimer Disease, Animals, Humans, Immunoglobulin G, Phagocytosis, Amyloid beta-Peptides, Microglia, Mice
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