Neuron-Specific Alterations in Signal Transduction Pathways associated with Alzheimer's Disease

Anne Gerschuetz; Helmut Heinsen; Edna Gruenblatt; Anne Kristin Wagner; Jasmin Bartl; Christoph Meissner; Andreas J. Fallgatter; Safa Al-Sarraj; Claire Troakes; Isidro Ferrer; Thomas Arzberger; Juergen Deckert; Peter Riederer; Matthias Fischer; Thomas Tatschner; Camelia Maria Monoranu

doi:10.3233/JAD-131280

Neuron-Specific Alterations in Signal Transduction Pathways associated with Alzheimer's Disease

Anne Gerschuetz, Helmut Heinsen, Edna Gruenblatt, Anne Kristin Wagner, Jasmin Bartl, Christoph Meissner, Andreas J. Fallgatter, Safa Al-Sarraj, Claire Troakes, Isidro Ferrer, Thomas Arzberger, Juergen Deckert, Peter Riederer, Matthias Fischer, Thomas Tatschner, Camelia Maria Monoranu^*

^*Corresponding author for this work

Basic and Clinical Neuroscience

Research output: Contribution to journal › Article › peer-review

29 Citations (Scopus)

Abstract

The hallmarks of sporadic Alzheimer's disease (AD) are extracellular amyloid deposits, intracellular neurofibrillary tangles (NFTs), and neuronal death. Hyperphosphorylation of tau is a key factor in the generation of NFTs. Mitogen activated protein kinase 1 (MAPK1) and protein kinase C beta (PRKCB) are thought to play a role in hyperphosphorylation, and PRCKB is thought to be involved in hypoxic stress and vascular dysfunction, and to trigger MAPK phosphorylation pathways. We performed single-cell analyses of neurons with different vulnerabilities to AD-related changes. Using quantitative PCR (qPCR), we measured the levels of MAPK1 and PRKCB transcript in CA1 (high vulnerability), CA2 pyramidal cells from the hippocampus, granule cells from the cerebellum (low vulnerability), and neurons from the brain stem (nucleus tractus spinalis nervi trigemini, characterized by early neurophysiological deficits) at progressive Braak stages compared to age-matched controls. The highly vulnerable CA1 pyramidal neurons were characterized by age-and disease-unrelated increases in PRCKB levels and by age-and disease-related increases in MAPK1 levels. In contrast, low PRKCB levels were found in CA2 pyramidal neurons, and MAPK1 levels were elevated in controls and intermediate AD stages. Both PRKCB and MAPK1 were increased in the late AD stages. MAPK1 and PRKCB levels were low in the brainstem and cerebellum. We propose that alterations in the expression of these two genes occur early in the pathogenesis of AD in a region-specific manner. In addition, multiple signal transduction pathways need to be affected to result in AD instead of physiological aging.

Original language	English
Pages (from-to)	135-142
Number of pages	8
Journal	JOURNAL OF ALZHEIMERS DISEASE
Volume	40
Issue number	1
DOIs	https://doi.org/10.3233/JAD-131280
Publication status	Published - Mar 2014

Keywords

Alzheimer's disease
MAPK1
neurodegeneration
PRKCB
selective vulnerability
signal transduction pathway
PROTEIN-KINASE-C
VAGUS NERVE-STIMULATION
FAR-FIELD POTENTIALS
BRAIN-STEM
NEUROFIBRILLARY TANGLES
HIPPOCAMPAL-FORMATION
PYRAMIDAL NEURON
MESSENGER-RNA
TAU-PROTEIN
CELLS

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Gerschuetz, A., Heinsen, H., Gruenblatt, E., Wagner, A. K., Bartl, J., Meissner, C., Fallgatter, A. J., Al-Sarraj, S., Troakes, C., Ferrer, I., Arzberger, T., Deckert, J., Riederer, P., Fischer, M., Tatschner, T., & Monoranu, C. M. (2014). Neuron-Specific Alterations in Signal Transduction Pathways associated with Alzheimer's Disease. JOURNAL OF ALZHEIMERS DISEASE, 40(1), 135-142. https://doi.org/10.3233/JAD-131280

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title = "Neuron-Specific Alterations in Signal Transduction Pathways associated with Alzheimer's Disease",

abstract = "The hallmarks of sporadic Alzheimer's disease (AD) are extracellular amyloid deposits, intracellular neurofibrillary tangles (NFTs), and neuronal death. Hyperphosphorylation of tau is a key factor in the generation of NFTs. Mitogen activated protein kinase 1 (MAPK1) and protein kinase C beta (PRKCB) are thought to play a role in hyperphosphorylation, and PRCKB is thought to be involved in hypoxic stress and vascular dysfunction, and to trigger MAPK phosphorylation pathways. We performed single-cell analyses of neurons with different vulnerabilities to AD-related changes. Using quantitative PCR (qPCR), we measured the levels of MAPK1 and PRKCB transcript in CA1 (high vulnerability), CA2 pyramidal cells from the hippocampus, granule cells from the cerebellum (low vulnerability), and neurons from the brain stem (nucleus tractus spinalis nervi trigemini, characterized by early neurophysiological deficits) at progressive Braak stages compared to age-matched controls. The highly vulnerable CA1 pyramidal neurons were characterized by age-and disease-unrelated increases in PRCKB levels and by age-and disease-related increases in MAPK1 levels. In contrast, low PRKCB levels were found in CA2 pyramidal neurons, and MAPK1 levels were elevated in controls and intermediate AD stages. Both PRKCB and MAPK1 were increased in the late AD stages. MAPK1 and PRKCB levels were low in the brainstem and cerebellum. We propose that alterations in the expression of these two genes occur early in the pathogenesis of AD in a region-specific manner. In addition, multiple signal transduction pathways need to be affected to result in AD instead of physiological aging.",

keywords = "Alzheimer's disease, MAPK1, neurodegeneration, PRKCB, selective vulnerability, signal transduction pathway, PROTEIN-KINASE-C, VAGUS NERVE-STIMULATION, FAR-FIELD POTENTIALS, BRAIN-STEM, NEUROFIBRILLARY TANGLES, HIPPOCAMPAL-FORMATION, PYRAMIDAL NEURON, MESSENGER-RNA, TAU-PROTEIN, CELLS",

author = "Anne Gerschuetz and Helmut Heinsen and Edna Gruenblatt and Wagner, {Anne Kristin} and Jasmin Bartl and Christoph Meissner and Fallgatter, {Andreas J.} and Safa Al-Sarraj and Claire Troakes and Isidro Ferrer and Thomas Arzberger and Juergen Deckert and Peter Riederer and Matthias Fischer and Thomas Tatschner and Monoranu, {Camelia Maria}",

year = "2014",

month = mar,

doi = "10.3233/JAD-131280",

language = "English",

volume = "40",

pages = "135--142",

journal = "JOURNAL OF ALZHEIMERS DISEASE",

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Gerschuetz, A, Heinsen, H, Gruenblatt, E, Wagner, AK, Bartl, J, Meissner, C, Fallgatter, AJ, Al-Sarraj, S , Troakes, C, Ferrer, I, Arzberger, T, Deckert, J, Riederer, P, Fischer, M, Tatschner, T & Monoranu, CM 2014, 'Neuron-Specific Alterations in Signal Transduction Pathways associated with Alzheimer's Disease', JOURNAL OF ALZHEIMERS DISEASE, vol. 40, no. 1, pp. 135-142. https://doi.org/10.3233/JAD-131280

TY - JOUR

T1 - Neuron-Specific Alterations in Signal Transduction Pathways associated with Alzheimer's Disease

AU - Gerschuetz, Anne

AU - Heinsen, Helmut

AU - Gruenblatt, Edna

AU - Wagner, Anne Kristin

AU - Bartl, Jasmin

AU - Meissner, Christoph

AU - Fallgatter, Andreas J.

AU - Al-Sarraj, Safa

AU - Troakes, Claire

AU - Ferrer, Isidro

AU - Arzberger, Thomas

AU - Deckert, Juergen

AU - Riederer, Peter

AU - Fischer, Matthias

AU - Tatschner, Thomas

AU - Monoranu, Camelia Maria

PY - 2014/3

Y1 - 2014/3

N2 - The hallmarks of sporadic Alzheimer's disease (AD) are extracellular amyloid deposits, intracellular neurofibrillary tangles (NFTs), and neuronal death. Hyperphosphorylation of tau is a key factor in the generation of NFTs. Mitogen activated protein kinase 1 (MAPK1) and protein kinase C beta (PRKCB) are thought to play a role in hyperphosphorylation, and PRCKB is thought to be involved in hypoxic stress and vascular dysfunction, and to trigger MAPK phosphorylation pathways. We performed single-cell analyses of neurons with different vulnerabilities to AD-related changes. Using quantitative PCR (qPCR), we measured the levels of MAPK1 and PRKCB transcript in CA1 (high vulnerability), CA2 pyramidal cells from the hippocampus, granule cells from the cerebellum (low vulnerability), and neurons from the brain stem (nucleus tractus spinalis nervi trigemini, characterized by early neurophysiological deficits) at progressive Braak stages compared to age-matched controls. The highly vulnerable CA1 pyramidal neurons were characterized by age-and disease-unrelated increases in PRCKB levels and by age-and disease-related increases in MAPK1 levels. In contrast, low PRKCB levels were found in CA2 pyramidal neurons, and MAPK1 levels were elevated in controls and intermediate AD stages. Both PRKCB and MAPK1 were increased in the late AD stages. MAPK1 and PRKCB levels were low in the brainstem and cerebellum. We propose that alterations in the expression of these two genes occur early in the pathogenesis of AD in a region-specific manner. In addition, multiple signal transduction pathways need to be affected to result in AD instead of physiological aging.

AB - The hallmarks of sporadic Alzheimer's disease (AD) are extracellular amyloid deposits, intracellular neurofibrillary tangles (NFTs), and neuronal death. Hyperphosphorylation of tau is a key factor in the generation of NFTs. Mitogen activated protein kinase 1 (MAPK1) and protein kinase C beta (PRKCB) are thought to play a role in hyperphosphorylation, and PRCKB is thought to be involved in hypoxic stress and vascular dysfunction, and to trigger MAPK phosphorylation pathways. We performed single-cell analyses of neurons with different vulnerabilities to AD-related changes. Using quantitative PCR (qPCR), we measured the levels of MAPK1 and PRKCB transcript in CA1 (high vulnerability), CA2 pyramidal cells from the hippocampus, granule cells from the cerebellum (low vulnerability), and neurons from the brain stem (nucleus tractus spinalis nervi trigemini, characterized by early neurophysiological deficits) at progressive Braak stages compared to age-matched controls. The highly vulnerable CA1 pyramidal neurons were characterized by age-and disease-unrelated increases in PRCKB levels and by age-and disease-related increases in MAPK1 levels. In contrast, low PRKCB levels were found in CA2 pyramidal neurons, and MAPK1 levels were elevated in controls and intermediate AD stages. Both PRKCB and MAPK1 were increased in the late AD stages. MAPK1 and PRKCB levels were low in the brainstem and cerebellum. We propose that alterations in the expression of these two genes occur early in the pathogenesis of AD in a region-specific manner. In addition, multiple signal transduction pathways need to be affected to result in AD instead of physiological aging.

KW - Alzheimer's disease

KW - MAPK1

KW - neurodegeneration

KW - PRKCB

KW - selective vulnerability

KW - signal transduction pathway

KW - PROTEIN-KINASE-C

KW - VAGUS NERVE-STIMULATION

KW - FAR-FIELD POTENTIALS

KW - BRAIN-STEM

KW - NEUROFIBRILLARY TANGLES

KW - HIPPOCAMPAL-FORMATION

KW - PYRAMIDAL NEURON

KW - MESSENGER-RNA

KW - TAU-PROTEIN

KW - CELLS

U2 - 10.3233/JAD-131280

DO - 10.3233/JAD-131280

M3 - Article

SN - 1387-2877

VL - 40

SP - 135

EP - 142

JO - JOURNAL OF ALZHEIMERS DISEASE

JF - JOURNAL OF ALZHEIMERS DISEASE

IS - 1

ER -

Neuron-Specific Alterations in Signal Transduction Pathways associated with Alzheimer's Disease

Abstract

Keywords

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