Genetic reduction of Nrf2 exacerbates cognitive deficits in a mouse model of Alzheimer's disease

Caterina Branca, Eric Ferreira, Thuy Vi Nguyen, Kristian Doyle, Antonella Caccamo, Salvatore Oddo

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Aging is the major risk factor for several neurodegenerative diseases, including Alzheimer's disease (AD). However, the mechanisms by which aging contributes to neurodegeneration remain elusive. The nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a transcription factor that regulates expression of a vast number of genes by binding to the antioxidant response element. Nrf2 levels decrease as a function of age, and reduced Nrf2 levels have been reported in postmortem human brains and animal models of AD. Nevertheless, it is still unknown whether Nrf2 plays a role in the cognitive deficits associated with AD. To address this question, we used a genetic approach to remove the Nrf2 gene from APP/PS1 mice, a widely used animal model of AD. We found that the lack of Nrf2 significantly exacerbates cognitive deficits in APP/PS1, without altering gross motor function. Specifically, we found an exacerbation of deficits in spatial learning and memory, as well as in working and associative memory. Different brain regions control these behavioral tests, indicating that the lack of Nrf2 has a global effect on brain function. The changes in cognition were linked to an increase in Aβ and interferon-gamma (IFNγ) levels, and microgliosis. The changes in IFNγ levels are noteworthy as previously published evidence indicates that IFNγ can increase microglia activation and induce Aβ production. Our data suggest a clear link between Nrf2 and AD-mediated cognitive decline and further strengthen the connection between Nrf2 and AD.

Original languageEnglish (US)
Pages (from-to)4823-4835
Number of pages13
JournalHuman Molecular Genetics
Volume26
Issue number24
DOIs
StatePublished - Dec 1 2017

Fingerprint

Alzheimer Disease
Interferon-gamma
Brain
Animal Models
Antioxidant Response Elements
Microglia
Short-Term Memory
Neurodegenerative Diseases
Cognition
Genes
Transcription Factors

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Genetic reduction of Nrf2 exacerbates cognitive deficits in a mouse model of Alzheimer's disease. / Branca, Caterina; Ferreira, Eric; Nguyen, Thuy Vi; Doyle, Kristian; Caccamo, Antonella; Oddo, Salvatore.

In: Human Molecular Genetics, Vol. 26, No. 24, 01.12.2017, p. 4823-4835.

Research output: Contribution to journalArticle

Branca, Caterina ; Ferreira, Eric ; Nguyen, Thuy Vi ; Doyle, Kristian ; Caccamo, Antonella ; Oddo, Salvatore. / Genetic reduction of Nrf2 exacerbates cognitive deficits in a mouse model of Alzheimer's disease. In: Human Molecular Genetics. 2017 ; Vol. 26, No. 24. pp. 4823-4835.
@article{7e12e43af8c440bfb1e3a00bed7dec1d,
title = "Genetic reduction of Nrf2 exacerbates cognitive deficits in a mouse model of Alzheimer's disease",
abstract = "Aging is the major risk factor for several neurodegenerative diseases, including Alzheimer's disease (AD). However, the mechanisms by which aging contributes to neurodegeneration remain elusive. The nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a transcription factor that regulates expression of a vast number of genes by binding to the antioxidant response element. Nrf2 levels decrease as a function of age, and reduced Nrf2 levels have been reported in postmortem human brains and animal models of AD. Nevertheless, it is still unknown whether Nrf2 plays a role in the cognitive deficits associated with AD. To address this question, we used a genetic approach to remove the Nrf2 gene from APP/PS1 mice, a widely used animal model of AD. We found that the lack of Nrf2 significantly exacerbates cognitive deficits in APP/PS1, without altering gross motor function. Specifically, we found an exacerbation of deficits in spatial learning and memory, as well as in working and associative memory. Different brain regions control these behavioral tests, indicating that the lack of Nrf2 has a global effect on brain function. The changes in cognition were linked to an increase in Aβ and interferon-gamma (IFNγ) levels, and microgliosis. The changes in IFNγ levels are noteworthy as previously published evidence indicates that IFNγ can increase microglia activation and induce Aβ production. Our data suggest a clear link between Nrf2 and AD-mediated cognitive decline and further strengthen the connection between Nrf2 and AD.",
author = "Caterina Branca and Eric Ferreira and Nguyen, {Thuy Vi} and Kristian Doyle and Antonella Caccamo and Salvatore Oddo",
year = "2017",
month = "12",
day = "1",
doi = "10.1093/hmg/ddx361",
language = "English (US)",
volume = "26",
pages = "4823--4835",
journal = "Human Molecular Genetics",
issn = "0964-6906",
publisher = "Oxford University Press",
number = "24",

}

TY - JOUR

T1 - Genetic reduction of Nrf2 exacerbates cognitive deficits in a mouse model of Alzheimer's disease

AU - Branca, Caterina

AU - Ferreira, Eric

AU - Nguyen, Thuy Vi

AU - Doyle, Kristian

AU - Caccamo, Antonella

AU - Oddo, Salvatore

PY - 2017/12/1

Y1 - 2017/12/1

N2 - Aging is the major risk factor for several neurodegenerative diseases, including Alzheimer's disease (AD). However, the mechanisms by which aging contributes to neurodegeneration remain elusive. The nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a transcription factor that regulates expression of a vast number of genes by binding to the antioxidant response element. Nrf2 levels decrease as a function of age, and reduced Nrf2 levels have been reported in postmortem human brains and animal models of AD. Nevertheless, it is still unknown whether Nrf2 plays a role in the cognitive deficits associated with AD. To address this question, we used a genetic approach to remove the Nrf2 gene from APP/PS1 mice, a widely used animal model of AD. We found that the lack of Nrf2 significantly exacerbates cognitive deficits in APP/PS1, without altering gross motor function. Specifically, we found an exacerbation of deficits in spatial learning and memory, as well as in working and associative memory. Different brain regions control these behavioral tests, indicating that the lack of Nrf2 has a global effect on brain function. The changes in cognition were linked to an increase in Aβ and interferon-gamma (IFNγ) levels, and microgliosis. The changes in IFNγ levels are noteworthy as previously published evidence indicates that IFNγ can increase microglia activation and induce Aβ production. Our data suggest a clear link between Nrf2 and AD-mediated cognitive decline and further strengthen the connection between Nrf2 and AD.

AB - Aging is the major risk factor for several neurodegenerative diseases, including Alzheimer's disease (AD). However, the mechanisms by which aging contributes to neurodegeneration remain elusive. The nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a transcription factor that regulates expression of a vast number of genes by binding to the antioxidant response element. Nrf2 levels decrease as a function of age, and reduced Nrf2 levels have been reported in postmortem human brains and animal models of AD. Nevertheless, it is still unknown whether Nrf2 plays a role in the cognitive deficits associated with AD. To address this question, we used a genetic approach to remove the Nrf2 gene from APP/PS1 mice, a widely used animal model of AD. We found that the lack of Nrf2 significantly exacerbates cognitive deficits in APP/PS1, without altering gross motor function. Specifically, we found an exacerbation of deficits in spatial learning and memory, as well as in working and associative memory. Different brain regions control these behavioral tests, indicating that the lack of Nrf2 has a global effect on brain function. The changes in cognition were linked to an increase in Aβ and interferon-gamma (IFNγ) levels, and microgliosis. The changes in IFNγ levels are noteworthy as previously published evidence indicates that IFNγ can increase microglia activation and induce Aβ production. Our data suggest a clear link between Nrf2 and AD-mediated cognitive decline and further strengthen the connection between Nrf2 and AD.

UR - http://www.scopus.com/inward/record.url?scp=85042914939&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85042914939&partnerID=8YFLogxK

U2 - 10.1093/hmg/ddx361

DO - 10.1093/hmg/ddx361

M3 - Article

C2 - 29036636

AN - SCOPUS:85042914939

VL - 26

SP - 4823

EP - 4835

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 24

ER -