ERK-mediated NGF signaling in the rat septo-hippocampal pathway diminishes with age

Brice J. Williams, Heather Bimonte-Nelson, Ann Charlotte Granholm-Bentley

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

Rationale: Degeneration of basal forebrain cholinergic neurons (BFCNs) plays an important role in aging and Alzheimer's disease (AD) pathology. This degeneration may be a result of disrupted nerve growth factor (NGF) signaling. Aged rats have memory deficits, BFCN degeneration, and disrupted NGF signaling. Objective: In this study we identify a rapid NGF signaling pathway in BFCNs and the second messenger system associated with that signaling. We also identify age-dependent alterations in this signaling pathway. Materials and methods: After cognitive assessment using the Morris water maze, rats were given an intra-hippocampal NGF injection. Basal forebrain immunohistochemical analysis, confocal microscopy, and inhibitor studies were performed. Results: An increase in immunoreactivity for the NGF receptor TrkA was found in cell bodies of BFCNs 15 min and 1 h post-NGF injection. Immunohistochemistry studies with phospho-ERK and phospho-AKT antibodies showed that this rapid signaling occurred through MAP kinase, but not PI-3 kinase pathways. MAPK inhibitor studies attenuated the NGF-induced effects. Both TrkA and phospho-ERK (extracellular signal-regulated kinase) immunoreactivities were diminished in aged rats and phospho-ERK immunoreactivity-correlated with aged rat performance in the Morris water maze. Conclusions: Rapid NGF signaling likely occurs in the rat CNS through the MAPK signaling pathway. This rapid signaling pathway is diminished in aged rats compared to young ones and may contribute to memory deficits observed in aged rats. As cholinergic degeneration coupled with altered levels of NGF and TrkA receptors are also seen in human aging and AD, ERK-related dysfunction may be relevant in human conditions as well.

Original languageEnglish (US)
Pages (from-to)605-618
Number of pages14
JournalPsychopharmacology
Volume188
Issue number4
DOIs
StatePublished - Nov 2006

Fingerprint

Nerve Growth Factor
Cholinergic Neurons
Memory Disorders
Alzheimer Disease
Nerve Growth Factor Receptors
Nerve Growth Factor Receptor
Nerve Degeneration
Injections
Water
Extracellular Signal-Regulated MAP Kinases
Second Messenger Systems
Phosphatidylinositol 3-Kinases
Confocal Microscopy
Cholinergic Agents
Phosphotransferases
Immunohistochemistry
Basal Forebrain
Pathology
Antibodies

Keywords

  • Aging
  • Cholinergic transmission
  • Growth factors
  • Memory loss
  • Second messenger signaling

ASJC Scopus subject areas

  • Pharmacology

Cite this

ERK-mediated NGF signaling in the rat septo-hippocampal pathway diminishes with age. / Williams, Brice J.; Bimonte-Nelson, Heather; Granholm-Bentley, Ann Charlotte.

In: Psychopharmacology, Vol. 188, No. 4, 11.2006, p. 605-618.

Research output: Contribution to journalArticle

Williams, Brice J. ; Bimonte-Nelson, Heather ; Granholm-Bentley, Ann Charlotte. / ERK-mediated NGF signaling in the rat septo-hippocampal pathway diminishes with age. In: Psychopharmacology. 2006 ; Vol. 188, No. 4. pp. 605-618.
@article{ac1f48576139473aa58f5d88deb434a5,
title = "ERK-mediated NGF signaling in the rat septo-hippocampal pathway diminishes with age",
abstract = "Rationale: Degeneration of basal forebrain cholinergic neurons (BFCNs) plays an important role in aging and Alzheimer's disease (AD) pathology. This degeneration may be a result of disrupted nerve growth factor (NGF) signaling. Aged rats have memory deficits, BFCN degeneration, and disrupted NGF signaling. Objective: In this study we identify a rapid NGF signaling pathway in BFCNs and the second messenger system associated with that signaling. We also identify age-dependent alterations in this signaling pathway. Materials and methods: After cognitive assessment using the Morris water maze, rats were given an intra-hippocampal NGF injection. Basal forebrain immunohistochemical analysis, confocal microscopy, and inhibitor studies were performed. Results: An increase in immunoreactivity for the NGF receptor TrkA was found in cell bodies of BFCNs 15 min and 1 h post-NGF injection. Immunohistochemistry studies with phospho-ERK and phospho-AKT antibodies showed that this rapid signaling occurred through MAP kinase, but not PI-3 kinase pathways. MAPK inhibitor studies attenuated the NGF-induced effects. Both TrkA and phospho-ERK (extracellular signal-regulated kinase) immunoreactivities were diminished in aged rats and phospho-ERK immunoreactivity-correlated with aged rat performance in the Morris water maze. Conclusions: Rapid NGF signaling likely occurs in the rat CNS through the MAPK signaling pathway. This rapid signaling pathway is diminished in aged rats compared to young ones and may contribute to memory deficits observed in aged rats. As cholinergic degeneration coupled with altered levels of NGF and TrkA receptors are also seen in human aging and AD, ERK-related dysfunction may be relevant in human conditions as well.",
keywords = "Aging, Cholinergic transmission, Growth factors, Memory loss, Second messenger signaling",
author = "Williams, {Brice J.} and Heather Bimonte-Nelson and Granholm-Bentley, {Ann Charlotte}",
year = "2006",
month = "11",
doi = "10.1007/s00213-006-0477-1",
language = "English (US)",
volume = "188",
pages = "605--618",
journal = "Psychopharmacology",
issn = "0033-3158",
publisher = "Springer Verlag",
number = "4",

}

TY - JOUR

T1 - ERK-mediated NGF signaling in the rat septo-hippocampal pathway diminishes with age

AU - Williams, Brice J.

AU - Bimonte-Nelson, Heather

AU - Granholm-Bentley, Ann Charlotte

PY - 2006/11

Y1 - 2006/11

N2 - Rationale: Degeneration of basal forebrain cholinergic neurons (BFCNs) plays an important role in aging and Alzheimer's disease (AD) pathology. This degeneration may be a result of disrupted nerve growth factor (NGF) signaling. Aged rats have memory deficits, BFCN degeneration, and disrupted NGF signaling. Objective: In this study we identify a rapid NGF signaling pathway in BFCNs and the second messenger system associated with that signaling. We also identify age-dependent alterations in this signaling pathway. Materials and methods: After cognitive assessment using the Morris water maze, rats were given an intra-hippocampal NGF injection. Basal forebrain immunohistochemical analysis, confocal microscopy, and inhibitor studies were performed. Results: An increase in immunoreactivity for the NGF receptor TrkA was found in cell bodies of BFCNs 15 min and 1 h post-NGF injection. Immunohistochemistry studies with phospho-ERK and phospho-AKT antibodies showed that this rapid signaling occurred through MAP kinase, but not PI-3 kinase pathways. MAPK inhibitor studies attenuated the NGF-induced effects. Both TrkA and phospho-ERK (extracellular signal-regulated kinase) immunoreactivities were diminished in aged rats and phospho-ERK immunoreactivity-correlated with aged rat performance in the Morris water maze. Conclusions: Rapid NGF signaling likely occurs in the rat CNS through the MAPK signaling pathway. This rapid signaling pathway is diminished in aged rats compared to young ones and may contribute to memory deficits observed in aged rats. As cholinergic degeneration coupled with altered levels of NGF and TrkA receptors are also seen in human aging and AD, ERK-related dysfunction may be relevant in human conditions as well.

AB - Rationale: Degeneration of basal forebrain cholinergic neurons (BFCNs) plays an important role in aging and Alzheimer's disease (AD) pathology. This degeneration may be a result of disrupted nerve growth factor (NGF) signaling. Aged rats have memory deficits, BFCN degeneration, and disrupted NGF signaling. Objective: In this study we identify a rapid NGF signaling pathway in BFCNs and the second messenger system associated with that signaling. We also identify age-dependent alterations in this signaling pathway. Materials and methods: After cognitive assessment using the Morris water maze, rats were given an intra-hippocampal NGF injection. Basal forebrain immunohistochemical analysis, confocal microscopy, and inhibitor studies were performed. Results: An increase in immunoreactivity for the NGF receptor TrkA was found in cell bodies of BFCNs 15 min and 1 h post-NGF injection. Immunohistochemistry studies with phospho-ERK and phospho-AKT antibodies showed that this rapid signaling occurred through MAP kinase, but not PI-3 kinase pathways. MAPK inhibitor studies attenuated the NGF-induced effects. Both TrkA and phospho-ERK (extracellular signal-regulated kinase) immunoreactivities were diminished in aged rats and phospho-ERK immunoreactivity-correlated with aged rat performance in the Morris water maze. Conclusions: Rapid NGF signaling likely occurs in the rat CNS through the MAPK signaling pathway. This rapid signaling pathway is diminished in aged rats compared to young ones and may contribute to memory deficits observed in aged rats. As cholinergic degeneration coupled with altered levels of NGF and TrkA receptors are also seen in human aging and AD, ERK-related dysfunction may be relevant in human conditions as well.

KW - Aging

KW - Cholinergic transmission

KW - Growth factors

KW - Memory loss

KW - Second messenger signaling

UR - http://www.scopus.com/inward/record.url?scp=34248530650&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=34248530650&partnerID=8YFLogxK

U2 - 10.1007/s00213-006-0477-1

DO - 10.1007/s00213-006-0477-1

M3 - Article

VL - 188

SP - 605

EP - 618

JO - Psychopharmacology

JF - Psychopharmacology

SN - 0033-3158

IS - 4

ER -