Selective degeneration of septal and hippocampal GABAergic neurons in a mouse model of amyloidosis and tauopathy
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by brain accumulation of amyloid-β peptide and neurofibrillary tangles, which are believed to initiate a pathological cascade that results in progressive impairment of cognitive functions and eventual neuronal death. To obta...
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doaj-4326d00f10c448618d2448f3727060a12021-03-22T12:38:23ZengElsevierNeurobiology of Disease1095-953X2012-07-01471112Selective degeneration of septal and hippocampal GABAergic neurons in a mouse model of amyloidosis and tauopathyDesirée Loreth0Laurence Ozmen1Florent G. Revel2Frédéric Knoflach3Philine Wetzel4Michael Frotscher5Friedrich Metzger6Oliver Kretz7Department of Neuroanatomy, University of Freiburg, GermanyRoche CNS Research and Early Development, Basel, SwitzerlandRoche CNS Research and Early Development, Basel, SwitzerlandRoche CNS Research and Early Development, Basel, SwitzerlandDepartment of Neuroanatomy, University of Freiburg, GermanyDepartment of Neuroanatomy, University of Freiburg, Germany; Center for Molecular Neurobiology Hamburg, University of Hamburg, GermanyRoche CNS Research and Early Development, Basel, SwitzerlandDepartment of Neuroanatomy, University of Freiburg, Germany; Corresponding author at: Department of Neuroanatomy, Center for Neurosciences, University of Freiburg, Albertstrasse 23, D-79104 Freiburg, Germany.Alzheimer's disease (AD) is a neurodegenerative disorder characterized by brain accumulation of amyloid-β peptide and neurofibrillary tangles, which are believed to initiate a pathological cascade that results in progressive impairment of cognitive functions and eventual neuronal death. To obtain a mouse model displaying the typical AD histopathology of amyloidosis and tauopathy, we generated a triple-transgenic mouse line (TauPS2APP) by overexpressing human mutations of the amyloid precursor protein, presenilin2 and tau genes. Stereological analysis of TauPS2APP mice revealed significant neurodegeneration of GABAergic septo-hippocampal projection neurons as well as their target cells, the GABAergic hippocampal interneurons. In contrast, the cholinergic medial septum neurons remained unaffected. Moreover, the degeneration of hippocampal GABAergic interneurons was dependent on the hippocampal subfield and interneuronal subtype investigated, whereby the dentate gyrus and the NPY-positive interneurons, respectively, were most strongly affected. Neurodegeneration was also accompanied by a change in the mRNA expression of markers for inhibitory interneurons. In line with the loss of inhibitory neurons, we observed functional changes in TauPS2APP mice relative to WT mice, with strongly enhanced long-term potentiation in the medial-perforant pathway input to the dentate gyrus, and stereotypic hyperactivity. Our data indicate that inhibitory neurons are the targets of neurodegeneration in a mouse model of amyloidosis and tauopathy, thus pointing to a possible role of the inhibitory network in the pathophysiological and functional cascade of Alzheimer's disease.http://www.sciencedirect.com/science/article/pii/S0969996112000824Alzheimer's diseaseTauAβGABADisinhibitionMedial septum |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Desirée Loreth Laurence Ozmen Florent G. Revel Frédéric Knoflach Philine Wetzel Michael Frotscher Friedrich Metzger Oliver Kretz |
spellingShingle |
Desirée Loreth Laurence Ozmen Florent G. Revel Frédéric Knoflach Philine Wetzel Michael Frotscher Friedrich Metzger Oliver Kretz Selective degeneration of septal and hippocampal GABAergic neurons in a mouse model of amyloidosis and tauopathy Neurobiology of Disease Alzheimer's disease Tau Aβ GABA Disinhibition Medial septum |
author_facet |
Desirée Loreth Laurence Ozmen Florent G. Revel Frédéric Knoflach Philine Wetzel Michael Frotscher Friedrich Metzger Oliver Kretz |
author_sort |
Desirée Loreth |
title |
Selective degeneration of septal and hippocampal GABAergic neurons in a mouse model of amyloidosis and tauopathy |
title_short |
Selective degeneration of septal and hippocampal GABAergic neurons in a mouse model of amyloidosis and tauopathy |
title_full |
Selective degeneration of septal and hippocampal GABAergic neurons in a mouse model of amyloidosis and tauopathy |
title_fullStr |
Selective degeneration of septal and hippocampal GABAergic neurons in a mouse model of amyloidosis and tauopathy |
title_full_unstemmed |
Selective degeneration of septal and hippocampal GABAergic neurons in a mouse model of amyloidosis and tauopathy |
title_sort |
selective degeneration of septal and hippocampal gabaergic neurons in a mouse model of amyloidosis and tauopathy |
publisher |
Elsevier |
series |
Neurobiology of Disease |
issn |
1095-953X |
publishDate |
2012-07-01 |
description |
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by brain accumulation of amyloid-β peptide and neurofibrillary tangles, which are believed to initiate a pathological cascade that results in progressive impairment of cognitive functions and eventual neuronal death. To obtain a mouse model displaying the typical AD histopathology of amyloidosis and tauopathy, we generated a triple-transgenic mouse line (TauPS2APP) by overexpressing human mutations of the amyloid precursor protein, presenilin2 and tau genes. Stereological analysis of TauPS2APP mice revealed significant neurodegeneration of GABAergic septo-hippocampal projection neurons as well as their target cells, the GABAergic hippocampal interneurons. In contrast, the cholinergic medial septum neurons remained unaffected. Moreover, the degeneration of hippocampal GABAergic interneurons was dependent on the hippocampal subfield and interneuronal subtype investigated, whereby the dentate gyrus and the NPY-positive interneurons, respectively, were most strongly affected. Neurodegeneration was also accompanied by a change in the mRNA expression of markers for inhibitory interneurons. In line with the loss of inhibitory neurons, we observed functional changes in TauPS2APP mice relative to WT mice, with strongly enhanced long-term potentiation in the medial-perforant pathway input to the dentate gyrus, and stereotypic hyperactivity. Our data indicate that inhibitory neurons are the targets of neurodegeneration in a mouse model of amyloidosis and tauopathy, thus pointing to a possible role of the inhibitory network in the pathophysiological and functional cascade of Alzheimer's disease. |
topic |
Alzheimer's disease Tau Aβ GABA Disinhibition Medial septum |
url |
http://www.sciencedirect.com/science/article/pii/S0969996112000824 |
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