Increased T cell reactivity to amyloid β protein in older humans and patients with Alzheimer disease

Monsonego, Alon; Zota, Victor; Karni, Arnon; Krieger, Jeffery I.; Bar-Or, Amit; Bitan, Gal; Budson, Andrew E.; Sperling, Reisa; Selkoe, Dennis J.; Weiner, Howard L.

doi:10.1172/jci200318104

Cited by 367Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsDementia and Cognitive Impairment Research

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Increased T cell reactivity to amyloid β protein in older humans and patients with Alzheimer disease

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Monsonego, Alon, Zota, Victor, Karni, Arnon, Krieger, Jeffery I., Bar-Or, Amit, Bitan, Gal, Budson, Andrew E., Sperling, Reisa, Selkoe, Dennis J., Weiner, Howard L.·2003·Journal of Clinical Investigation

DOI 10.1172/jci200318104PMC PMC166296

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Abstract

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)
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Microglia 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)
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T 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: Monsonego, Alon
Zota, Victor
Karni, Arnon
Bitan, Gal
Budson, Andrew E.
Sperling, Reisa
Selkoe, Dennis J.
Weiner, Howard L.
Venue: Journal of Clinical Investigation
Publisher: American Society for Clinical Investigation
Published: 2003-08-01
Volume: 112
Issue: 3
Pages: 415-422
ISSN: 0021-9738 (ISSN-L)
DOI: 10.1172/jci200318104
PMC: PMC166296
OpenAlex: W4252526962
Cited by: 367
References: 7
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: Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › 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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Increased T cell reactivity to amyloid β protein in older humans and patients with Alzheimer disease

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