NeuroMolecular Medicine

, Volume 9, Issue 4, pp 340–354 | Cite as

Increased T-cell Reactivity and Elevated Levels of CD8+ Memory T-cells in Alzheimer’s Disease-patients and T-cell Hyporeactivity in an Alzheimer’s Disease-mouse Model: Implications for Immunotherapy

  • Katharina Schindowski
  • Anne Eckert
  • Jürgen Peters
  • Corinna Gorriz
  • Uta Schramm
  • Thomas Weinandi
  • Konrad Maurer
  • Lutz Frölich
  • Walter E. Müller
Original Paper

Abstract

Neuroinflammation is observed in neurodegenerative diseases like Alzheimer’s disease (AD). However, a little is known about the mechanisms of neural-immune interactions. The involvement of peripheral T-cell function in AD is still far from clear, though it plays an important role in immunotherapy. The aim of this study was to determine peripheral T-cell reactivity in AD patients and in an AD mouse model. Mitogenic activation via ligation of the T-cell receptor (TCR) with PHA-L was measured in T lymphocytes from AD patients and Thy1(APP751SL) × HMG(PS1M146L)-transgenic mice (APP × PS1). In order to uncover failures in TCR signaling, the TCR was also bypassed by PMA and ionomycin treatment. All patients were sporadic late onset cases and the transgenic mice expressed no mutant APP in lymphocytes, so that direct interactions of mutant APP on T-cell function can be excluded. CD4+ and CD8+ T-cell showed increased reactivity (tyrosine phosphorylation, CD69 expression, and proliferation) in AD, while APP × PS1 transgenic mice displayed hyporeactive CD8+ T-cells after TCR ligation. Increased levels of CD8+ T memory cells and down regulation of CD8 receptor were found in AD and the animal model. Anergic TCR uncoupling was associated with loss of MAPK signaling (p38, ERK1 and ERK2) in APP × PS1. Our data implicate the generation of reactive memory T-cell in AD and of anergic memory T-cells in transgenic mice and should be taken into concern when designing immunotherapy.

Keywords

Neurodegeneration CD3 Activation-induced cell death (AICD) CD69 BrdU 4G10 Apoliporotein E (ApoE) Neuroinflammation Hyposensitive Neural–immune interaction 

Abbreviations

7-AAD

7-Amino actinomycin

AD

Alzheimer’s disease

ApoE

Apoliporotein E

APP

Amyloid precursor protein

BrdU

Brom-3′desoxy-uridine

CD

Cluster of differentiation

CNS

Central nervous system

FITC

Fluorescein isothiocyanate

FSC

Forward scatter

I

Ionomycin

MMSE

Mini mental state examination score

MAPK

Mitogen-activated protein kinase

MS

Multiple sclerosis

n.s.

Not statistically significant

n.d.

Not determined

PBMC

Peripheral blood mononuclear cells

PE

Phycoerythrin

PerCp

Peridin chlorophyll

PHA-L

Lectin from Phaseolus vulgaris Leucoagglutinin

PMA

Phorbol 12-myristate 13-acetate

PS1

Presenilin-1

SSC

Side scatter

Th

T helper

vs.

Versus

Notes

Acknowledgments

This work was supported by grants from Dr. Robert Pfleger Stiftung, Alzheimer Initiative e.V., Hirnliga e.V. and a Marie-Curie fellowship to KS. Disclosure statement: This study was approved by the responsible Ethical Committee and in accordance with standards of the guide for the care and use of laboratory animals and with respect to European Community rules.

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Copyright information

© Humana Press Inc. 2007

Authors and Affiliations

  • Katharina Schindowski
    • 1
    • 2
  • Anne Eckert
    • 1
    • 3
  • Jürgen Peters
    • 4
  • Corinna Gorriz
    • 4
  • Uta Schramm
    • 4
  • Thomas Weinandi
    • 4
  • Konrad Maurer
    • 4
  • Lutz Frölich
    • 4
    • 5
  • Walter E. Müller
    • 1
  1. 1.Institute of Pharmacology, Biocenter building N260Johann Wolfgang-Goethe-UniversityFrankfurt am MainGermany
  2. 2.INSERM, U837, Faculté de Médecine, Institut de Médecine Prédictive et Recherche ThérapeutiqueUniversité Lille 2Lille CedexFrance
  3. 3.Psychiatric University Clinic BaselBaselSwitzerland
  4. 4.Department of Psychiatry and Psychotherapy IJohann Wolfgang-Goethe-UniversityFrankfurt am MainGermany
  5. 5.Central Institute for Mental Health, Department for Gerontopsychiatry, Faculty for clinical medicineUniversity HeidelbergMannheimGermany

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