ArticleProceedings of the National Academy of Sciences of the United States of America2016
The adaptive immune system restrains Alzheimer's disease pathogenesis by modulating microglial function.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 256 papers, 2 of them syntheses that pooled it.
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Who cites it
256 citing papers in PubMed, 2 syntheses or guidelines pooled it, 411 citations in OpenAlex.
- Meta-Analysis of Transcriptomic Studies of Blood and Six Brain Regions Identifies a Consensus of 15 Cross-Tissue Mechanisms in Alzheimer's Disease and Suggests an Origin of Cross-Study Heterogeneity.American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics · 2025Pooled it
- Transcriptomics Meta-Analysis Reveals Phagosome and Innate Immune System Dysfunction as Potential Mechanisms in the Cortex of Alzheimer's Disease Mouse Strains.Journal of molecular neuroscience : MN · 2023Pooled it
- uPAR exhibits age- and region-dependent expression in the brains of mice with Alzheimer's disease-like pathology.Brain research · 2026Article
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- Neurodegenerative diseases and immune system: From pathogenic mechanism to therapy.Neural regeneration research · 2026Article
- Gamma-type immunoglobulin enhances phagocytosis of amyloid-beta fibrils by microglia.Neural regeneration research · 2026Article
- Clinical rationale for thymic restoration in adult immunosenescence.Immunity & ageing : I & A · 2026Review
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- Neonatal estradiol influences regional gene expression for early sex-specific inflammatory responses in the 5xFAD mouse model.Biology of sex differences · 2026Article
- Adaptive immunity in the pathogenesis of neurodegeneration.Nature immunology · 2026Review
- Zika virus infection in the brains of lymphocyte-deficient mice does not lead to neurological symptoms despite sustained high viral load.Journal of neurovirology · 2026Article
- The Immune-Chemokine Axis in Alzheimer's Disease: Roles of Adaptive Immune System in Neuroinflammation and Disease Progression.Biomolecules · 2026Review
- Therapeutic targeting of neuroimmune mechanisms in neurodegeneration.Nature reviews. Drug discovery · 2026Review
- Type I interferon drives T cell responses to amyloid beta in the central nervous system.Nature communications · 2026Article
- Review
- 5xFAD-NSG mice: a preclinical Alzheimer model for human cell therapy studies.bioRxiv : the preprint server for biology · 2026Article
- Lung memory B cells ameliorate Alzheimer's disease-like pathology in 5×FAD mice through the CXCL12-CXCR4 axis.Acta pharmacologica Sinica · 2026Article
- Engineering chimeric antigen receptor CD4 T cells for Alzheimer's disease.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Evidence for reduced somatic T-cell receptor sequence diversity profiles among Midwestern Amish in an aging cohort study.medRxiv : the preprint server for health sciences · 2026Article
196 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
13 authors at 2 institutions in 1 country.
Funding
Abstract
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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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.