Elsevier

Behavioural Brain Research

Volume 318, 1 February 2017, Pages 18-23
Behavioural Brain Research

Research report
Maternal separation exacerbates Alzheimer’s disease-like behavioral and pathological changes in adult APPswe/PS1dE9 mice

https://doi.org/10.1016/j.bbr.2016.10.030Get rights and content

Highlights

  • Maternal separation exacerbates adult APPswe/PS1dE9 mice learning and memory deficits.

  • Maternal separation increases senile plaques deposition in cortex and hippocampus in APPswe/PS1dE9 mice.

  • Maternal separation decreases cholinergic neurons in nucleus basalis of Meynert in APPswe/PS1dE9 mice.

Abstract

Alzheimer’s disease (AD), the most common neurodegenerative disorder that gradually destroys memory and cognitive abilities in the elderly, makes a huge emotional and economic burden on the patients and their families. The presence of senile plaques and the loss of cholinergic neurons in the brain are two neuropathological hallmarks of AD. Maternal separation (MS) is an animal paradigm designed to make early life stress. Studies on wild type rodents showed that MS could induce AD-like cognitive deficit and pathological changes. However, the effects of MS on AD susceptible population or AD animal models are still unclear. In the present study, male APPswe/PS1dE9 transgenic mice were separated from dam and pups 3 h per day from postnatal day 2 to day 21. After weaning, all animals were housed under normal conditions (4 mice per cage). At 9-month age, MWM tests were performed to evaluate the learning and memory abilities. Then the pathological changes in the brain were measured by histology staining. The results showed MS mice had more severe deficit of learning and memory. Compared to the control, there were more senile plaques in cortex and hippocampus, fewer cholinergic neurons in nucleus basalis of Meynert in MS mice. These results indicate that MS exacerbates Alzheimer’s disease-like behavioral and pathological changes in APPswe/PS1dE9 mice.

Introduction

Alzheimer’s disease (AD) is a progressive, irreversible brain disorder which is clinically characterized by an accelerated loss of memory and deterioration of other cognitive functions, including learning ability [1], [2]. With the elderly population increasing steadily, AD is becoming a huge emotional and economic burden on the patients, their families and the society as a whole [3], [4].

Senile plaques and loss of cholinergic neuron are two neuropathological hallmarks of AD [5], [6]. The principal constituent of senile plaques is amyloid-β protein (Aβ), which is generated from amyloid precursor protein (APP) and plays a crucial role in AD development [7], [8], [9], [10]. AD patients exhibit selective loss of cholinergic neurons in the brains, especially in nucleus basalis of Meynert [11]. Both the increased Aβ and loss of cholinergic neuron are believed to contribute to cognitive decline in AD [12], [13].

Although the exact etiology of AD remains unknown, clinical and animal experimental researches suggested that stress was a risk factor for AD [14], [15] and stress-related psychiatric disorders had been identified as a risk for developing AD [16], [17], [18], [19], [20], [21], [22].

Maternal separation (MS) is an animal paradigm designed to mimic repeated exposure to stress during early life [23], [24]. Stress during early life could disrupt the maternal-infants relationship and lead to long-lasting deleterious effects on brain neurodevelopment and on the network of biological systems [25]. Studies on wild type mouse and rat showed that MS could induce AD-like cognitive deficit and pathological changes [26], [27], [28], [29]. So we speculated that MS might exacerbate these abnormal changes in the AD susceptible population, especially those who had familial Alzheimer disease (FAD) inherent gene. To prove this, in the present study, APPswe/PS1dE9 double transgenic mice were used to explore the effects of MS on their behavioral and pathological changes.

Section snippets

Animals

In this study, the experimental procedures involving animals were performed in accordance with the guidelines for the Regulations of the Experimental Animal Administration issued by the State Committee of Science and Technology of the People’s Republic of China. All efforts were made to minimize animals’ suffering.

APPswe/PS1dE9 mice were purchased from the Model Animal Research Center of Nanjing University (Nanjing, China). Mice were raised at 22–25 °C and 50–60% relative humidity under a 12-h

MS decreased spatial learning and memory in APPswe/PS1dE9 mice

Morris water maze tests were used to assess the spatial learning and memory functions. During spatial navigation trial, the MS and the control mice exhibited no significant differences in the first 3 days (P > 0.05). However, on day 4 and day 5, the latencies of MS mice were longer than that of control (P < 0.05, Fig. 1A).

The probe trial was performed at 24 h after the navigation trials. As shown in Fig 1B, the MS mice spent less time (15.81 ± 0.26 s) in the target quadrant (the platform quadrant in the

Discussion

Infancy is a critical period for brain development. Stress experience during this period increases Aβ level in brain [28] and exacerbates the age-related cognitive decline [38], [39]. MS rodent is a well-characterized model of early-life stress, in which pups are deprived from dam for a single or repeated periods during early life [23]. However, the effects of MS on senile plaques in cortex and cholinergic neurons in basal forebrain in AD susceptible people, e.g. in the group with family

References (73)

  • S.Y. Shin et al.

    Adolescent mice show anxiety- and aggressive-like behavior and the reduction of long-term potentiation in mossy fiber −CA3 synapses after neonatal maternal separation

    Neuroscience

    (2016)
  • H. Jin et al.

    Aβ-HBc virus-like particlesimmunization without additional adjuvant ameliorates the learning and memory and reduces. Aβ deposit in PDAPP mice

    Vaccine

    (2014)
  • B. Laursen et al.

    Cholinergic degeneration is associated with increased plaque deposition and cognitive impairment in APPswe/PS1dE9 mice

    Behav. Brain Res.

    (2013)
  • H.J. Huang et al.

    Long-term social isolation exacerbates the impairment of spatial working memory in APP/PS1 transgenic mice

    Brain Res.

    (2011)
  • S. Teipel et al.

    Cholinergic basal forebrain atrophy predicts amyloid burden in Alzheimer’s disease

    Neurobiol. Aging

    (2014)
  • K.T. Wirz et al.

    Cortical beta amyloid protein triggers an immune response, but no synaptic changes in the APPswe/PS1dE9 Alzheimer’s disease mouse model

    Neurobiol. Aging

    (2013)
  • D.J. Selkoe

    The cell biology of beta-amyloid precursor protein and presenilin in Alzheimer’s disease

    Trends Cell Biol.

    (1998)
  • R. Wang et al.

    Presenilin 1 familial Alzheimer’s disease mutation leads to defective associative learning and impaired adult neurogenesis

    Neuroscience

    (2004)
  • M. Garcia-Alloza et al.

    Characterization of amyloid deposition in the APPswe/PS1dE9 mouse model of Alzheimer disease

    Neurobiol. Dis.

    (2006)
  • 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)
  • T.P. O’Leary et al.

    Visuo-spatial learning and memory deficits on the Barnes maze in the 16-month-old APPswe/PS1dE9 mouse model of Alzheimer’s disease

    Behav. Brain Res.

    (2009)
  • M. Izco et al.

    Changes in the brain and plasma Aβ peptide levels with age and its relationship with cognitive impairment in the APPswe/PS1dE9 mouse model of Alzheimer’s disease

    Neuroscience

    (2014)
  • S.A. Ferguson et al.

    Longitudinal behavioral changes in the APP/PS1 transgenic Alzheimer's disease model

    Behav. Brain Res.

    (2013)
  • R. Schliebs et al.

    The cholinergic system in aging and neuronal degeneration

    Behav. Brain Res.

    (2011)
  • D.S. Auld et al.

    Alzheimer's disease and the basal forebrain cholinergic system: relations to beta-amyloid peptides, cognition, and treatment strategies

    Prog. Neurobiol.

    (2002)
  • D. Puzzo et al.

    Behavioral assays with mouse models of Alzheimer’s disease: practical considerations and guidelines

    Biochem. Pharmacol.

    (2014)
  • C.L. Gonzalez et al.

    Differential participation of NBM in the acquisition and retrieval of conditioned taste aversion and Morris water maze

    Behav. Brain Res.

    (2000)
  • H. Frielingsdorf et al.

    The septohippocampal cholinergic system and spatial working memory in the Morris water maze

    Behav. Brain Res.

    (2006)
  • A. Grimm et al.

    Alzheimer mitochondria and gender

    Neurosci. Biobehav. Rev.

    (2016)
  • G. Waldemar et al.

    Recommendations for the diagnosis and management of Alzheimer's disease and other disorders associated with dementia: EFNS guideline

    Eur. J. Neurol.

    (2007)
  • Alzheimer’s Association

    Alzheimer’s disease facts and figures

    Alzheimers Dement.

    (2014)
  • C. Qiu et al.

    Epidemiology of Alzheimer’s disease: occurrence, determinants, and strategies toward intervention

    Dialogues Clin. Neurosci.

    (2009)
  • T. Jiang et al.

    Epidemiology and etiology of Alzheimer’s disease: from genetic to non-genetic factors

    Curr. Alzheimer Res.

    (2013)
  • S. Kar et al.

    Interactions between beta-amyloid and central cholinergic neurons: implications for Alzheimer’s disease

    J. Psychiatry Neurosci.

    (2004)
  • J. Hardy et al.

    The amyloid hypothesis of Alzheimer’s disease:progress and problems on the road to therapeutics

    Science

    (2002)
  • T.G. Beach

    Physiologic origins of age-related beta-amyloid deposition

    Neurodegener. Dis.

    (2008)
  • Cited by (23)

    • Tannic acid inhibits lipopolysaccharide-induced cognitive impairment in adult mice by targeting multiple pathological features

      2022, International Immunopharmacology
      Citation Excerpt :

      Increase level of SAB indicates less memory deficits and better cognitive activity, whereas the reduce level of SAB shows decrease working memory [56]. The Morris water maze (MWM) test is used to assess spatial learning and memory and the damage to particular cortical areas of the brain in rodents [57]. Acquisition of spatial information was tested during training trials of MWM task and memory retention was evaluated in probe trials.

    • Effects of Early Life Adversities upon Memory Processes and Cognition in Rodent Models

      2022, Neuroscience
      Citation Excerpt :

      Some studies using middle-aged or aged animals point to an acceleration of age- related impairments, since effects on behavior and on LTP not observed in younger adults appear in ELS-exposed aged animals (Oitzl et al., 2000; Brunson et al., 2005; Ivy et al., 2010; Solas et al., 2010; Suri et al., 2014; Lesuis et al., 2019a; Short et al., 2020). Besides, levels of amyloid beta peptide (the principal constituent of amyloid plaques in Alzheimer’s disease), and of beta-secretase 1 (BACE1, the major enzyme for the generation of amyloid beta peptide) are increased in the hippocampus of MS aged animals (Solas et al., 2010), and increased deposition of senile plaques in the cerebral cortex and hippocampus have been observed in middle-aged animals subjected to early adversities (Hui et al., 2017; Lesuis et al., 2019b), as well as decreased cholinergic neurons in the nucleus basalis of Meynert (Hui et al., 2017), all of these findings suggesting accelerated neurodegeneration. On the other hand, in agreement with what was reported for behavioral tasks and HPA axis control, reports on the effects of early handling suggest a preservation of cognitive function as the animals age (Meaney et al., 1991; Vallée et al., 1999; Lesuis et al., 2017).

    • Attenuation of spatial memory in 5xFAD mice by targeting cholinesterases, oxidative stress and inflammatory signaling using 2-(hydroxyl-(2-nitrophenyl)methyl)cyclopentanone

      2021, International Immunopharmacology
      Citation Excerpt :

      A high level of SAB shows less memory impairment and better cognitive function, while the decrease level of SAB indicates less working memory [88]. The Morris water maze (MWM) task is used for the assessment of spatial learning and memory in rodents; also it can be used to investigate the damage to particular cortical regions of the brain [89]. In the MWM task, during training trials spatial information acquisition was assessed, while in probe trials memory retention was determined.

    • Early-life stress induces the development of Alzheimer's disease pathology via angiopathy

      2021, Experimental Neurology
      Citation Excerpt :

      Some studies have evaluated the effects of early life experiences on later age- and AD-related processes in rodents (Lesuis et al., 2018). Three or more hours of daily separation from the mother during early life can disrupt continuity in maternal care, resulting in stress in mouse pups (Franklin et al., 2012), and can accelerate AD-like pathology in AD model mice (Hui et al., 2017). Although several theories for this accelerated pathology have been proposed, they do not adequately explain the changes in AD-related processes.

    View all citing articles on Scopus
    View full text