Elsevier

Neurobiology of Aging

Volume 34, Issue 11, November 2013, Pages 2551-2563
Neurobiology of Aging

Regular article
Impact of N-tau on adult hippocampal neurogenesis, anxiety, and memory

https://doi.org/10.1016/j.neurobiolaging.2013.05.010Get rights and content

Abstract

Different pathological tau species are involved in memory loss in Alzheimer's disease, the most common cause of dementia among older people. However, little is known about how tau pathology directly affects adult hippocampal neurogenesis, a unique form of structural plasticity implicated in hippocampus-dependent spatial learning and mood-related behavior. To this aim, we generated a transgenic mouse model conditionally expressing a pathological tau fragment (26–230 aa of the longest human tau isoform, or N-tau) in nestin-positive stem/progenitor cells. We found that N-tau reduced the proliferation of progenitor cells in the adult dentate gyrus, reduced cell survival and increased cell death by a caspase-3–independent mechanism, and recruited microglia. Although the number of terminally differentiated neurons was reduced, these showed an increased dendritic arborization and spine density. This resulted in an increase of anxiety-related behavior and an impairment of episodic-like memory, whereas less complex forms of spatial learning remained unaltered. Understanding how pathological tau species directly affect neurogenesis is important for developing potential therapeutic strategies to direct neurogenic instructive cues for hippocampal function repair.

Introduction

The neurobiological substrate of learning and memory resides in modifications of synaptic strength and structural changes of neural networks activated during learning. Adult neurogenesis, the birth and development of new neurons in the adult brain, represents a unique form of structural and functional plasticity found in the hippocampal dentate gyrus (DG) and subventricular zone (SVZ) of lateral ventricles. DG is a critical structure for learning and memory functions (Deng et al., 2010; Emsley et al., 2005; Inokuchi et al., 2011). The capacity to encode and retain memories is severely compromised in dementia. Alzheimer's disease (AD) is the most common cause of dementia in elderly people, characterized by synaptic pathology, intracellular accumulation of tau protein in neurofibrillary tangles, tau spreading, extracellular accumulation of β-amyloid in senile plaques, and loss of specific neuronal populations. Although these lesions and cognitive dysfunction are poorly correlated, the former may be directly involved, individually or in combination, in damaging brain plasticity in vulnerable regions of the brain (Ittner et al., 2010).

Abnormalities in tau protein—such as hyperphosphorylation, mutation, truncation, oligomerization, aggregation, as well as imbalance in isoform ratios (Chatterjee et al., 2009; Jackson et al., 2002; Santacruz et al., 2005)—are sufficient to cause synaptic dysfunction, neurodegeneration, and dementia. Among tau abnormalities, we focused on the N-terminal 26–230 tau fragment (N-tau). Different lines of evidence support a role for this fragment in the impairment of neuronal plasticity and neurodegeneration: (1) N-tau is generated by caspase and/or calpain in different in vitro and in vivo models of AD (Canu et al., 1998; Corsetti et al., 2008; Park and Ferreira, 2005); (2) it is expressed in human AD brains (Amadoro et al., 2012; Rohn et al., 2002); (3) it is toxic when overexpressed in primary neuronal cultures (notably, the mechanism of toxicity involves the NMDAR and the signal transduction pathways linked to the activation of this receptor, like that of mitogen-activated protein [MAP] kinases) (Amadoro et al., 2006); and (4) a similar tau product, originating by an alternative splicing of exon 6, abundant in fetal brains and in CA1/CA3 pyramidal cells and DG granular cells of adult hippocampus, is supposed to be involved in the morphogenesis of synapses and neuronal networks, as well as in morphogenetic apoptosis (Luo et al., 2004).

The subgranular zone (SGZ) of the DG is characterized by the presence of progenitor cells that produce, by a highly regulated process, glutamatergic neurons for the entire life of the organism. These neurons populate the granule cell layer of the DG and become functionally integrated into the existing DG circuitry (Kempermann et al., 2004a, 2004b). Studies have correlated adult DG neurogenesis with cognitive function and hippocampus-mediated learning and memory (Deng et al., 2010). Moreover, it is believed that the abnormal regulation of adult hippocampal neurogenesis might account for cognitive deterioration in neurodegenerative diseases associated with dementia (Lazarov et al., 2010; Mu and Gage, 2011).

Alterations in the amyloid precursor protein (APP) and tau metabolism may indirectly perturb the permissive cues within the neurogenic niche that drive the production of new neurons and their subsequent integration into the neurocircuitry of the brain (Ghosal et al., 2010; Haughey et al., 2002; Rodriguez et al., 2008). Less studied, however, are the direct effects on adult hippocampal neurogenesis of proteins that, as tau, regulate the morphogenesis and functional integration of new neurons (Bullmann et al., 2007; Fuster-Matanzo et al., 2012; Hong et al., 2010).

With this aim, we investigated the link between pathological N-tau and adult neurogenesis, by means of a novel conditional transgenic mouse model expressing N-tau in neuronal precursor cells. Here we report the effect of N-tau expression in neuronal precursor cells, and we demonstrate that significant loss of nestin-positive neuronal stem cells and terminally differentiated newborn neurons was coupled with increased anxiety-related behavior in stressful conditions and deficit in episodic-like memory, both documented at the early onset of Alzheimer's disease.

Section snippets

Mouse lines and genotyping

The bi-transgenic nestin-rtTA/TRE-N-tau mouse line (henceforth referred to as TgN-tau) is the progeny of 2 mouse lines, each carrying a transgene: (1) nestin-rtTA transgene, encoding the tetracycline-regulated transactivator (rtTA) protein driven by the rat nestin intron II enhancer/promoter, previously generated (Mitsuhashi et al., 2001), which restricts reporter gene expression to neuronal tissue (Fukuda et al., 2003, Kronenberg et al., 2003; Yamaguchi et al., 2000); and (2) TRE-N-tau

Doxycycline treatment in bi-transgenic N-tau mice induces expression of N-tau in nestin-positive neuronal precursor cells

N-tau conditional expression was induced in nestin-expressing adult hippocampal stem and progenitor cells (Kempermann et al., 2004a, 2004b) of TgN-tau mice from P60 through administration of Dox (Fig. 1A). The analysis of the expression of transgenic N-tau in P95 mice with active N-tau transgene (TgN-tau ON mice) indicated targeting to the DG, as visualized by X-gal staining, which revealed the β-galactosidase activity of the β-geo reporter gene fused to the nestin-rtTA transgene (Fig. 1B). In

Discussion

Here we present a murine model that is, to our knowledge, the first specifically aimed to analyze the direct effects of the overexpression of a pathological tau species on adult hippocampal neurogenesis.

Our model is based on the selective and conditional expression in adult neural precursor cells of the N-terminal–26-230 fragment of the longest human tau isoform (Canu et al., 1998) using the Tet-On system under the control of nestin promoter.

The activation of the transgene resulted in the

Disclosure statement

The authors declare no potential conflicts of interest.

Acknowledgements

We thank F.H. Gage for providing the CAG-GFP viral vector, L. Micheli for suggestions in the retrovirus production, and A. Graziani for mouse tail biopsy. This work was supported by grants from Italian Ministry of Education, University and Research (PRIN 2009, 2009KP83CR-02; 2009KP83CR-03; 2009KP83CR-01 to N.C., E.M., and V.C., respectively) and from the Italian Ministry of Economy (Project FaReBio; to F.T.). D.S. was supported by the Guardia di Finanza—Italian Ministry of Economy.

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