Defects of immune regulation in the presenilin-1 mutant knockin mouse

Grant A. Morgan, Qing Guo, Sic L. Chan, Devin S. Gary, Barbara A. Osborne, Mark P. Mattson

Research output: Contribution to journalArticle

Abstract

Mutations in the presenilin-1 (PS1) gene are causally linked to early-onset Alzheimer's disease (AD). Studies of neurons suggest that PS1 mutations result in a gain-of-function, which perturbs calcium regulation and increases cell vulnerability to apoptosis. Alterations in immune cell function have also been demonstrated in AD, and a role for PS1 in immune regulation has been suggested recently. We now report that splenocytes from PS1-mutant (M146V) knockin mice exhibit increased caspase activity, abnormal calcium regulation and aberrant mitochondrial function. Isolated splenic T cells from PS1-mutant mice respond poorly to proliferative signals and have downregulated cluster designation 3 and interleukin (IL)- 2-receptor expression necessary for a normal T-cell immune response. Thus, adverse effects of a mutation that causes AD on immune function that involves perturbed calcium regulation and cytokine signaling in lymphocytes, and associated sensitivity of lymphocytes to apoptosis are demonstrated. These findings suggest that abnormalities in immune function might play major roles in the pathogenesis of AD.

Original languageEnglish (US)
Pages (from-to)35-46
Number of pages12
JournalNeuroMolecular Medicine
Volume9
Issue number1
DOIs
StatePublished - Feb 2007

Fingerprint

Presenilin-1
Alzheimer Disease
Calcium
Mutation
Lymphocytes
Apoptosis
T-Lymphocytes
Interleukin-2 Receptors
Caspases
Down-Regulation
Cytokines
Neurons
Genes

ASJC Scopus subject areas

  • Neuroscience(all)
  • Genetics
  • Cell Biology

Cite this

Morgan, G. A., Guo, Q., Chan, S. L., Gary, D. S., Osborne, B. A., & Mattson, M. P. (2007). Defects of immune regulation in the presenilin-1 mutant knockin mouse. NeuroMolecular Medicine, 9(1), 35-46. https://doi.org/10.1385/NMM:9:1:35

Defects of immune regulation in the presenilin-1 mutant knockin mouse. / Morgan, Grant A.; Guo, Qing; Chan, Sic L.; Gary, Devin S.; Osborne, Barbara A.; Mattson, Mark P.

In: NeuroMolecular Medicine, Vol. 9, No. 1, 02.2007, p. 35-46.

Research output: Contribution to journalArticle

Morgan, GA, Guo, Q, Chan, SL, Gary, DS, Osborne, BA & Mattson, MP 2007, 'Defects of immune regulation in the presenilin-1 mutant knockin mouse', NeuroMolecular Medicine, vol. 9, no. 1, pp. 35-46. https://doi.org/10.1385/NMM:9:1:35
Morgan GA, Guo Q, Chan SL, Gary DS, Osborne BA, Mattson MP. Defects of immune regulation in the presenilin-1 mutant knockin mouse. NeuroMolecular Medicine. 2007 Feb;9(1):35-46. https://doi.org/10.1385/NMM:9:1:35
Morgan, Grant A. ; Guo, Qing ; Chan, Sic L. ; Gary, Devin S. ; Osborne, Barbara A. ; Mattson, Mark P. / Defects of immune regulation in the presenilin-1 mutant knockin mouse. In: NeuroMolecular Medicine. 2007 ; Vol. 9, No. 1. pp. 35-46.
@article{31a7d0c06b0044fc9b4c901e4917fbfe,
title = "Defects of immune regulation in the presenilin-1 mutant knockin mouse",
abstract = "Mutations in the presenilin-1 (PS1) gene are causally linked to early-onset Alzheimer's disease (AD). Studies of neurons suggest that PS1 mutations result in a gain-of-function, which perturbs calcium regulation and increases cell vulnerability to apoptosis. Alterations in immune cell function have also been demonstrated in AD, and a role for PS1 in immune regulation has been suggested recently. We now report that splenocytes from PS1-mutant (M146V) knockin mice exhibit increased caspase activity, abnormal calcium regulation and aberrant mitochondrial function. Isolated splenic T cells from PS1-mutant mice respond poorly to proliferative signals and have downregulated cluster designation 3 and interleukin (IL)- 2-receptor expression necessary for a normal T-cell immune response. Thus, adverse effects of a mutation that causes AD on immune function that involves perturbed calcium regulation and cytokine signaling in lymphocytes, and associated sensitivity of lymphocytes to apoptosis are demonstrated. These findings suggest that abnormalities in immune function might play major roles in the pathogenesis of AD.",
author = "Morgan, {Grant A.} and Qing Guo and Chan, {Sic L.} and Gary, {Devin S.} and Osborne, {Barbara A.} and Mattson, {Mark P.}",
year = "2007",
month = "2",
doi = "10.1385/NMM:9:1:35",
language = "English (US)",
volume = "9",
pages = "35--46",
journal = "NeuroMolecular Medicine",
issn = "1535-1084",
publisher = "Humana Press",
number = "1",

}

TY - JOUR

T1 - Defects of immune regulation in the presenilin-1 mutant knockin mouse

AU - Morgan, Grant A.

AU - Guo, Qing

AU - Chan, Sic L.

AU - Gary, Devin S.

AU - Osborne, Barbara A.

AU - Mattson, Mark P.

PY - 2007/2

Y1 - 2007/2

N2 - Mutations in the presenilin-1 (PS1) gene are causally linked to early-onset Alzheimer's disease (AD). Studies of neurons suggest that PS1 mutations result in a gain-of-function, which perturbs calcium regulation and increases cell vulnerability to apoptosis. Alterations in immune cell function have also been demonstrated in AD, and a role for PS1 in immune regulation has been suggested recently. We now report that splenocytes from PS1-mutant (M146V) knockin mice exhibit increased caspase activity, abnormal calcium regulation and aberrant mitochondrial function. Isolated splenic T cells from PS1-mutant mice respond poorly to proliferative signals and have downregulated cluster designation 3 and interleukin (IL)- 2-receptor expression necessary for a normal T-cell immune response. Thus, adverse effects of a mutation that causes AD on immune function that involves perturbed calcium regulation and cytokine signaling in lymphocytes, and associated sensitivity of lymphocytes to apoptosis are demonstrated. These findings suggest that abnormalities in immune function might play major roles in the pathogenesis of AD.

AB - Mutations in the presenilin-1 (PS1) gene are causally linked to early-onset Alzheimer's disease (AD). Studies of neurons suggest that PS1 mutations result in a gain-of-function, which perturbs calcium regulation and increases cell vulnerability to apoptosis. Alterations in immune cell function have also been demonstrated in AD, and a role for PS1 in immune regulation has been suggested recently. We now report that splenocytes from PS1-mutant (M146V) knockin mice exhibit increased caspase activity, abnormal calcium regulation and aberrant mitochondrial function. Isolated splenic T cells from PS1-mutant mice respond poorly to proliferative signals and have downregulated cluster designation 3 and interleukin (IL)- 2-receptor expression necessary for a normal T-cell immune response. Thus, adverse effects of a mutation that causes AD on immune function that involves perturbed calcium regulation and cytokine signaling in lymphocytes, and associated sensitivity of lymphocytes to apoptosis are demonstrated. These findings suggest that abnormalities in immune function might play major roles in the pathogenesis of AD.

UR - http://www.scopus.com/inward/record.url?scp=33751120668&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33751120668&partnerID=8YFLogxK

U2 - 10.1385/NMM:9:1:35

DO - 10.1385/NMM:9:1:35

M3 - Article

C2 - 17114823

AN - SCOPUS:33751120668

VL - 9

SP - 35

EP - 46

JO - NeuroMolecular Medicine

JF - NeuroMolecular Medicine

SN - 1535-1084

IS - 1

ER -