Increased T cell reactivity to amyloid β protein in older humans and patients with Alzheimer disease
Open accessAbstract
Alzheimer disease (AD) is characterized by the progressive deposition of the 42-residue amyloid beta protein (Abeta) in brain regions serving memory and cognition. In animal models of AD, immunization with Abeta results in the clearance of Abeta deposits from the brain. However, a trial of vaccination with synthetic human Abeta1-42 in AD resulted in the development of meningoencephalitis in some patients. We measured cellular immune responses to Abeta in middle-aged and elderly healthy subjects and in patients with AD. A significantly higher proportion of healthy elderly subjects and patients with AD had strong Abeta-reactive T cell responses than occurred in middle-aged adults. The immunodominant Abeta epitopes in humans resided in amino acids 16-33. Epitope mapping enabled the identification of MHC/T cell receptor (TCR) contact residues. The occurrence of intrinsic T cell reactivity to the self-antigen Abeta in humans has implications for the design of Abeta vaccines, may itself be linked to AD susceptibility and course, and appears to be associated with the aging process.
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In the AD brain, chronic activation of microglia is associated with inflammatory cytokines including TNFα that can substantially block the ability of microglia to remove or degrade Aβ.
“Within the AD brain, there is a chronic activation of microglia associated with inflammatory cytokines including TNF␣ that can substantially block of ability of the microglia to remove 47,49,50 or degrade A. 51,52”
From CX3CR1 Deficiency Alters Microglial Activation and Reduces Beta-Amyloid Deposition in Two Alzheimer's Disease Mouse Models (2010) · cites this paper as [50]
The Introduction associates AD plaques with activated microglia and describes microgliosis and elevated cytokines as inflammatory changes in AD (page not available). It does not identify TNFα or say that inflammatory cytokines block microglia from removing or degrading Aβ. The discussion instead describes TGF-β promoting microglial clearance in transgenic mice. (LLM, conf=0.84)
Experimental — accuracy not yet measuredMicroglia can serve as antigen-presenting cells for Aβ-reactive T cells.
“In vitro data showed a ‘cross-talking’ between microglia and T cells, microglia can serve as antigen-presenting cells for Aβ-reactive T cells and, in turn, T cells themselves can influence microglial differentiation [161–163].”
From PKR, the double stranded RNA‐dependent protein kinase as a critical target in Alzheimer's disease (2009) · cites this paper as [162]
The discussion following Figure 4 says Aβ is processed and presented by antigen-presenting cells to Aβ-reactive T cells. It also proposes that local APCs in the brain may capture Aβ, but it does not identify those cells as microglia or show microglia presenting Aβ to T cells. (LLM, conf=0.84)
Experimental — accuracy not yet measuredT cells can influence microglial differentiation.
“In vitro data showed a ‘cross-talking’ between microglia and T cells, microglia can serve as antigen-presenting cells for Aβ-reactive T cells and, in turn, T cells themselves can influence microglial differentiation [161–163].”
From PKR, the double stranded RNA‐dependent protein kinase as a critical target in Alzheimer's disease (2009) · cites this paper as [162]
In the passage labeled Figure 4 (page unavailable), the paper suggests that Aβ-reactive T cells might modulate microglial activation at plaque sites. It does not report that T cells influence microglial differentiation, or present in vitro data demonstrating that effect. (LLM, conf=0.83)
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- Authors
- Monsonego, A., Zota, V., Karni, A., Krieger, J. I., Bar-Or, A., Bitan, G., Budson, A. E., Sperling, R., Selkoe, D. J., & Weiner, H. L.
- Affiliations
- Brigham and Women's Hospital (US)
- Corresponding author
- Weiner, Howard L.
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2003-08-01
- Volume
- 112
- Issue
- 3
- Pages
- 415-422
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC166296
- OpenAlex
- W4252526962
- Cited by
- 367
- References
- 4
- Citations by year
- 2026: 15 · 2025: 21 · 2024: 17 · 2023: 19 · 2022: 15 · 2021: 20 · 2020: 14 · 2019: 13 · 2018: 14 · 2017: 12 · 2016: 9 · 2015: 15 · 2014: 8 · 2013: 18 · 2012: 12
- FWCI
- 10.95
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Alzheimer's Association
- Foundation for Neurologic Diseases
- National Institutes of Health
- 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, amyloid-beta, T cell response, cell-mediated immunity, immunosenescence, aging, epitope mapping, immunodominant epitopes, meningoencephalitis, autoantigens
- MeSH terms
- Adult, Aged, Aged, 80 and over, Aging, Alzheimer Disease, Animals, Autoantigens, Binding Sites, Female, Humans, Immunity, Cellular, Male, Middle Aged, Peptide Fragments, T-Lymphocytes, Case-Control Studies, Cytokines, Amyloid beta-Peptides, Epitope Mapping, Amino Acid Substitution, Alzheimer Vaccines
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