Selective degeneration of septal and hippocampal GABAergic neurons in a mouse model of amyloidosis and tauopathy

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Abstract

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.

Highlights

► We analyzed neurodegeneration in a triple transgenic Alzheimer's disease mouse model. ► We found a degeneration of inhibitory neurons in the septum and hippocampus. ► Impaired inhibitory network resulted in increased LTP and behavioural alterations. ► This suggests a role of the GABAergic network in the pathophysiology of AD.

Introduction

Alzheimer's disease (AD) is the most common neurodegenerative condition in adult humans, characterized by a slow-progressing decline in cognitive function that results in dementia and eventually death. AD is clinically divided into an early onset or familial (FAD) form, and a sporadic or late onset form (SAD). FAD is associated with genetic mutations in amyloid precursor protein (APP) and presenilin (PS) 1 or 2 (Bertram and Tanzi, 2005, Goate, 2006, Sherrington et al., 1995), making models based on these human mutations highly relevant for investigations on the pathophysiology of FAD. The late-onset cases have been ascribed to apolipoprotein E (APOE) gene mutations that are now considered to be the most important risk factor for the development of SAD (Bertram et al., 2010, Corder et al., 1993, Strittmatter et al., 1993). The histopathological changes occurring in the brains of AD patients include the formation of β-amyloid plaques and tau neurofibrillary tangles. Accordingly, transgenic mouse lines expressing mutated forms of APP, PS or tau provide suitable models for the investigation of AD pathophysiology. However, when mice transgenically express mutated APP either alone or in combination with PS, there is an increase both in Aβ levels and plaque formation, but no development of tau neurofibrillary tangles (Games et al., 1995, Holcomb et al., 1998, Hsiao et al., 1996, Sturchler-Pierrat et al., 1997). While mutations in human tau are yet to be reported in AD patients, tau dysfunction has been linked to neurodegeneration in frontotemporal dementia (Hutton et al., 1998). Moreover, mice overexpressing mutated forms of tau show neurofibrillary pathology and neurodegeneration (Götz and Ittner, 2008). Thus, in order to establish a mouse model displaying the relevant histopathological features of AD, we recently generated a triple-transgenic mouse line (TauPS2APP) expressing mutated forms of tau, PS2 and APP (Grueninger et al., 2010). These mice display an age-dependent accumulation of Aβ, with formation of Aβ-plaques and neurofibrillary tangles in the hippocampus. Notably, accumulation of Aβ in TauPS2APP mice leads to accelerated tau pathology and increased phosphorylation of tau at serine 422 when compared to tau single-transgenic mice. Moreover, TauPS2APP mice are hyperactive and show impaired spatial learning in the Morris water maze. However, stereological analysis of pyramidal neurons within the hippocampus did not reveal any signs of neuronal loss (Grueninger et al., 2010). In the present study, we provide a comprehensive analysis of neurodegeneration in TauPS2APP mice in the basal forebrain, an important source of GABAergic and cholinergic input for the hippocampus, and in the hippocampus itself. In addition, we performed electrophysiological characterization of TauPS2APP mice, as well as an age-dependent evaluation of their behavioral activity. Our results show that GABAergic neurons undergo neurodegeneration in a triple transgenic mouse model for amyloidosis and tauopathy, thus suggesting a role for the inhibitory network in the pathophysiology of AD.

Section snippets

Transgenic mice

The transgenic APP (line 147.72H) is homozygous for the human APP Swedish FAD transgene, the transgenic PS2 (line PS2.30H) is homozygous for human PS2 N141I and the transgenic PS2APP (line B6.152H) is homozygous for both human PS2 N141I and APP Swedish FAD transgenes. The double transgenic mouse line was created by co-injection of both transgenes into C57BL/6 zygotes, as previously described (Ozmen et al., 2009). The transgenic TauP301L mouse (line pR5) was generated on a mixed C57Bl/6, DBA/2

GABAergic but not cholinergic septo-hippocampal projection neurons undergo neurodegeneration

In 18-month-old TauPS2APP mice, the diameter of the fornix at the level of the columna (Figs. 1a–c) and at the level of the fimbria fornicis (Figs. 1d–f) was reduced by ~ 50% and ~ 20%, respectively, when compared to WT controls. Since the fimbria-fornix largely comprises the axons of septo-hippocampal projection neurons, the age-dependent reduction in fornix diameter led us to the assumption that these projection neurons undergo progressive degeneration in TauPS2APP mice. We thus performed

Discussion

The present study provides a morphological and functional characterization of a recently-generated triple-transgenic mouse model for amyloidosis and tauopathy (TauPS2APP), whereby the major phenotypical finding was selective neurodegeneration of GABAergic neurons both in the hippocampus and medial septum complex. The selective affection of the GABAergic septo-hippocampal population but relative sparing of the cholinergic system within the basal forebrain is somewhat surprising. Three decades

Acknowledgments

The authors thank S. Nestel, M. Haenggi, J. Messer and P. Biry for skilful technical assistance, J.-L. Moreau and T. Ballard for their valuable guidance as well as S. Dieni for proofreading the manuscript. MF is Senior Research Professor of the Hertie Foundation.

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