Elsevier

Neurobiology of Aging

Volume 57, September 2017, Pages 220-231
Neurobiology of Aging

Regular article
Differential alteration of hippocampal function and plasticity in females and males of the APPxPS1 mouse model of Alzheimer's disease

https://doi.org/10.1016/j.neurobiolaging.2017.05.025Get rights and content

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by memory loss and impaired cognitive functions. The higher incidence of AD among women indicates that sex is one of the main risk factor for developing the disease. Using the transgenic amyloid precursor protein × presenilin 1 (APPxPS1) mouse model of AD, we investigated sex inequality with regards to memory capacities and hippocampal plasticity. We report that spatial memory is strongly affected in APPxPS1 females while remarkably spared in males, at all ages tested. Given the contribution of adult neurogenesis to hippocampal-dependent memory processes, we examined whether impaired neurogenesis could account for age-related decline of memory functions in APPxPS1 mice. We show that not only limited numbers of new neurons are generated in these mice, but also, that new granule cells display reduced capacity for synaptic connectivity, a default that is exacerbated in females. Moreover, high densities of hypertrophic astrocytes are observed in the dentate gyrus of APPxPS1 females specifically. By revealing sex-dependent hippocampal alterations, our data may provide causal explanation to APPxPS1 females' memory deficits.

Introduction

Alzheimer's disease (AD) is a neurodegenerative disorder, and to date the primary cause of dementia in the aging population. AD is clinically characterized by cognitive and memory impairments, and histologically by the appearance of amyloid beta (Aβ) deposits, neurofibrillary tangles, and neuronal loss in brain regions associated with learning and memory, such as the cortex and hippocampus (Reitz et al., 2009, Serrano-Pozo et al., 2011). Whether and how these features of AD induce deleterious cognitive effects are not fully elucidated yet. However, several studies have suggested that alteration of synaptic plasticity in the brain, and specifically in the hippocampus, could explain memory impairments in AD (Ma and Klann, 2012, Narayan et al., 2015). In the dentate gyrus of the hippocampus, neurogenesis occurs throughout life and gives rise to new neurons that become functionally integrated and contribute to memory processes (Marín-Burgin and Schinder, 2012). The incorporation of adult-generated functional neurons into existing hippocampal neural networks provides a higher capacity for plasticity, and favors the encoding and storage of memories (Kropff et al., 2015).

In AD patients, quantification of neurogenic markers in post mortem tissue has initially led to contradictory results and interpretations (Boekhoorn et al., 2006, Jin et al., 2003, Zhang et al., 2008). Recently, a better understanding was provided by reports showing that adult hippocampal neurogenesis is differentially affected during disease progression (Ekonomou et al., 2015, Gomez-Nicola et al., 2014, Perry et al., 2012). Interestingly, at the functional level, low proliferation and differentiation capacities of adult hippocampal stem cells were correlated with memory dysfunction in human (Coras et al., 2010). In amyloidogenic mouse models of AD which exhibit cognitive deficits, a general picture has emerged indicating that adult hippocampal neurogenesis is altered (Demars et al., 2010, Faure et al., 2011, Krezymon et al., 2013, Shruster et al., 2010, Verret et al., 2007). In these models, impairments of adult hippocampal neurogenesis seem to precede or occur early in the time-course of the disease, suggesting that they may contribute to the cognitive alterations observed in these animals.

The incidence of Alzheimer's disease in human also indicates that sex is one of the main risk factor for developing the disease. Indeed, clinical and preclinical studies report that women carry a higher risk of developing AD compared with men (Barron and Pike, 2012, Vest and Pike, 2013). In line with these data, a larger accumulation of Aβ was observed in females compared with males in several AD mouse models including the Tg2576 (Callahan et al., 2001, Lee et al., 2002), 3xTG-AD (Carroll et al., 2010), and amyloid precursor protein × presenilin 1 (APPxPS1; Halford and Russell, 2009, Sierksma et al., 2013, Wang et al., 2003) mice. Higher levels of circulating Aβ and broader Aβ plaque load have been reported in APPxPS1 females (Gallagher et al., 2013, Sierksma et al., 2012, Taniuchi et al., 2007) and are paralleled with spatial memory deficits in these mice (Gallagher et al., 2013, Sierksma et al., 2013).

In the present work, we question whether hippocampal cellular alterations, including adult neurogenesis impairments, may also differ between sexes in these APPxPS1 mice and could provide further causal explanation for memory deficits. The main finding of our study is that APPxPS1 females, but not males, exhibit spatial memory impairments that are paralleled with hippocampal cellular alterations. These cellular changes include deficits of adult neurogenesis and a robust astroglial activation in the dentate gyrus.

Section snippets

Animals

Male and female APPsw695/PS1dE9 mice were generated as previously described (Jankowsky et al., 2004). Briefly, 2 lines of transgenic mice were used. Line C3-3 expresses chimeric mouse APP with the Swedish mutation K670N/M671L and humanized Aβ domain (Borchelt et al., 1996, Borchelt et al., 1997). Line S-9 expresses the exon 9–deleted variant of human PS1 (Jankowsky et al., 2004, Lee et al., 1997). Both transgenes are active in the central nervous system under the control of the mouse prion

Hippocampal-dependent memory is impaired in APPxPS1 females, but intact in males

APPxPS1 males and females of 7–9 months of age and their nontransgenic littermates were subjected to either object location task or object recognition task, thus assessing, respectively, the hippocampal-dependent and -independent forms of memory (Fig. 1A and B). During the acquisition phase in the object location task, all 4 groups of mice spent similar amounts of time in exploring the objects (Supporting Information Fig. S1), indicating a same exploratory drive among mice, irrespective of

Discussion

In this study, we investigated sex-related differences in the expression and severity of Alzheimer's disease pathology, in the widely used APPxPS1 mouse model (Borchelt et al., 1997, Jankowsky et al., 2004). We evidenced that APPxPS1 females, but not males, exhibit spatial memory impairments that are paralleled with cellular alterations in their hippocampus. These cellular changes include deficits of adult neurogenesis and a robust astroglial activation in the dentate gyrus.

Epidemiologic

Disclosure statement

The authors have no actual or potential conflicts of interest.

Acknowledgements

The authors thank Dr J. L. Jankowsky for graciously providing the APP and PS1 mice founders, H. Halley for breeding and genotyping the APPxPS1 mice. Mice were housed in the ABC Facility of ANEXPLO Toulouse. Confocal images were acquired at the LITC (light imaging toulouse CBI) Imaging Facility in Toulouse, France.

This work was supported by grants from the Agence Nationale de la Recherche to C. R. (ThalaMe, ANR-14-CE13-0029-03; SIMI7, GRAL-12-BS07-0011); the France Alzheimer Association (2015);

References (85)

  • A. Hamilton et al.

    The effect of ageing on neurogenesis and oxidative stress in the APP(swe)/PS1(deltaE9) mouse model of Alzheimer's disease

    Brain Res.

    (2012)
  • B. Hattiangady et al.

    Aging does not alter the number or phenotype of putative stem/progenitor cells in the neurogenic region of the hippocampus

    Neurobiol. Aging

    (2008)
  • N. Kee et al.

    The utility of Ki-67 and BrdU as proliferative markers of adult neurogenesis

    J. Neurosci. Methods

    (2002)
  • D.L. King et al.

    Progressive and gender-dependent cognitive impairment in the APP(SW) transgenic mouse model for Alzheimer's disease

    Behav. Brain Res.

    (1999)
  • R.A. Kohman et al.

    Neurogenesis, inflammation and behavior

    Brain Behav. Immun.

    (2013)
  • A. Koulakoff et al.

    Glial connexin expression and function in the context of Alzheimer's disease

    Biochim. Biophys. Acta

    (2012)
  • E. Kropff et al.

    Dynamic role of adult-born dentate granule cells in memory processing

    Curr. Opin. Neurobiol.

    (2015)
  • M. Liebmann et al.

    Astrocytic Cx43 and Cx30 differentially modulate adult neurogenesis in mice

    Neurosci. Lett.

    (2013)
  • A. Marín-Burgin et al.

    Requirement of adult-born neurons for hippocampus-dependent learning

    Behav. Brain Res.

    (2012)
  • L. Meda et al.

    Glial activation in Alzheimer's disease: the role of Abeta and its associated proteins

    Neurobiol. Aging

    (2001)
  • X. Mei et al.

    Astroglial connexin immunoreactivity is specifically altered at β-amyloid plaques in β-amyloid precursor protein/presenilin1 mice

    Neuroscience

    (2010)
  • T. Melnikova et al.

    Sex-related dimorphism in dentate gyrus atrophy and behavioral phenotypes in an inducible tTa:APPsi transgenic model of Alzheimer's disease

    Neurobiol. Dis.

    (2016)
  • R. Moraga-Amaro et al.

    Role of astrocytes in memory and psychiatric disorders

    J. Physiol. Paris

    (2014)
  • R.E. Mrak et al.

    Glia and their cytokines in progression of neurodegeneration

    Neurobiol. Aging

    (2005)
  • D.G. Mumby et al.

    Dissociation in retrograde memory for object discriminations and object recognition in rats with perirhinal cortex damage

    Behav. Brain Res.

    (2002)
  • P.J. Narayan et al.

    Increased acetyl and total histone levels in post-mortem Alzheimer's disease brain

    Neurobiol. Dis.

    (2015)
  • E.K. Perry et al.

    Neurogenic abnormalities in Alzheimer's disease differ between stages of neurogenesis and are partly related to cholinergic pathology

    Neurobiol. Dis.

    (2012)
  • P.J. Pistell et al.

    Acquisition of conditioned taste aversion is impaired in the amyloid precursor protein/presenilin 1 mouse model of Alzheimer's disease

    Neuroscience

    (2008)
  • J. Puoliväli et al.

    Hippocampal A beta 42 levels correlate with spatial memory deficit in APP and PS1 double transgenic mice

    Neurobiol. Dis.

    (2002)
  • A. Ruitenberg et al.

    Incidence of dementia: does gender make a difference?

    Neurobiol. Aging

    (2001)
  • A. Savonenko et al.

    Episodic-like memory deficits in the APPswe/PS1dE9 mouse model of Alzheimer's disease: relationships to β-amyloid deposition and neurotransmitter abnormalities

    Neurobiol. Dis.

    (2005)
  • A. Serrano-Pozo et al.

    Reactive glia not only associates with plaques but also parallels tangles in Alzheimer's disease

    Am. J. Pathol.

    (2011)
  • J.G. Sheng et al.

    Human brain S100b and S100b mRNA expression increases with age: Pathogenic implications for Alzheimer's disease

    Neurobiol. Aging

    (1996)
  • A.S. Sierksma et al.

    Behavioral and neurobiological effects of prenatal stress exposure in male and female APPswe/PS1dE9 mice

    Neurobiol. Aging

    (2013)
  • A.S. Sierksma et al.

    Effects of prenatal stress exposure on soluble Aβ and brain-derived neurotrophic factor signaling in male and female APPswe/PS1dE9 mice

    Neurochem. Int.

    (2012)
  • J.L. Spencer et al.

    Uncovering the mechanisms of estrogen effects on hippocampal function

    Front Neuroendocrinol.

    (2008)
  • S. Sultan et al.

    Synaptic integration of adult-born hippocampal neurons is locally Controlled by astrocytes

    Neuron

    (2015)
  • M. Theis et al.

    Emerging complexities in identity and function of glial connexins

    Trends Neurosci.

    (2005)
  • R.S. Vest et al.

    Gender, sex steroid hormones, and Alzheimer's disease

    Horm. Behav.

    (2013)
  • J. Wang et al.

    Gender differences in the amount and deposition of amyloidβ in APPswe and PS1 double transgenic mice

    Neurobiol. Dis.

    (2003)
  • M.D. Wu et al.

    Adult murine hippocampal neurogenesis is inhibited by sustained IL-1β and not rescued by voluntary running

    Brain Behav. Immun.

    (2012)
  • L.L. Barnes et al.

    Sex differences in the clinical manifestations of Alzheimer disease pathology

    Arch. Gen. Psychiatry

    (2005)
  • Cited by (25)

    • Impaired plasticity of intrinsic excitability in the dentate gyrus alters spike transfer in a mouse model of Alzheimer's disease

      2021, Neurobiology of Disease
      Citation Excerpt :

      Concomitantly, APP/PS1 female mice displayed impaired contextual fear conditioning and object location task, two hippocampus-dependent memory tasks. These results are in general agreement with other studies reporting impairments of CFC in APP/PS1 mice as early as 4–6 months of age (Kilgore et al., 2010; Bonardi et al., 2011; Janus et al., 2015) and OLT in APP/PS1 female mice of 7–9 months of age (Richetin et al., 2017). Regardless of the age, APP/PS1 mice in our study were not significantly more active than the aged-matched WT.

    • Role of glial cells in the generation of sex differences in neurodegenerative diseases and brain aging

      2021, Mechanisms of Ageing and Development
      Citation Excerpt :

      For instance, metabolic factors can contribute to sex differences in brain aging and although higher body mass index is associated with greater brain deterioration with aging in humans, this association is stronger in men than in women (Armstrong et al., 2019; Alqarni et al., 2020; Chin Fatt et al., 2020). The degeneration or malfunctioning of neurons is the most obvious cause of the cognitive, affective, and behavioral deficits associated to brain disorders and aging, with sex-specific modifications in neurons (McEwen, 2002; Richetin et al., 2017; Giacobini and Pepeu, 2018; Arsenault et al., 2020) possibly explaining some of the differences between males and females in brain deterioration associated to pathology and aging. However, the focus of the present analysis will be on the role played by another cellular component of the nervous system in this sex-specific deterioration: the glial cells.

    View all citing articles on Scopus
    View full text