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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

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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.

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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

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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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Author notes

  1. Anne Eckert

    Present address: Psychiatric University Clinic Basel, Maiengasse 16, Basel, 4056, Switzerland

  2. Lutz Frölich

    Present address: Central Institute for Mental Health, Department for Gerontopsychiatry, Faculty for clinical medicine, University Heidelberg, J 5, 68159, Mannheim, Germany

Authors and Affiliations

  1. Institute of Pharmacology, Biocenter building N260, Johann Wolfgang-Goethe-University, Max-von-Laue-Strasse 9, 60438, Frankfurt am Main, Germany

    Katharina Schindowski, Anne Eckert & Walter E. Müller

  2. INSERM, U837, Faculté de Médecine, Institut de Médecine Prédictive et Recherche Thérapeutique, Université Lille 2, 1 Place de Verdun, Lille Cedex, 59045, France

    Katharina Schindowski

  3. Department of Psychiatry and Psychotherapy I, Johann Wolfgang-Goethe-University, Heinrich-Hoffmann-Strasse 10, 60528, Frankfurt am Main, Germany

    Jürgen Peters, Corinna Gorriz, Uta Schramm, Thomas Weinandi, Konrad Maurer & Lutz Frölich

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  1. Katharina Schindowski
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Correspondence to Katharina Schindowski.

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Schindowski, K., Eckert, A., Peters, J. et al. 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. Neuromol Med 9, 340–354 (2007). https://doi.org/10.1007/s12017-007-8015-9

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