Regular articleDifferential alteration of hippocampal function and plasticity in females and males of the APPxPS1 mouse model of Alzheimer's disease
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.
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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);
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