Elsevier

Behavioural Brain Research

Volume 347, 16 July 2018, Pages 300-313
Behavioural Brain Research

Behavioral and psychological symptoms of dementia (BPSD) and impaired cognition reflect unsuccessful neuronal compensation in the pre-plaque stage and serve as early markers for Alzheimer’s disease in the APP23 mouse model

https://doi.org/10.1016/j.bbr.2018.03.030Get rights and content

Highlights

  • Impaired soft skills and cognition in APP23 model of pre-plaque Alzheimer’s disease.

  • Deficits accompanied by unsuccessful neuronal compensation.

  • Enriched Environment (EE) alleviates detected symptoms of Alzheimer’s disease.

  • Observed symptoms can serve as early disease markers and EE as a therapy.

Abstract

Recent research on Alzheimer’s disease (AD) focuses on processes prior to amyloid-beta plaque deposition accounting for the progress of the disease. However, early mechanisms of AD are still poorly understood and predictors of the disease in the pre-plaque stage essential for initiating an early therapy are lacking. Behavioral and psychological symptoms of dementia (BPSD) and potentially impaired cognition may serve as predictors and early clinical diagnostic markers for AD. To investigate potential BPSD and cognitive impairments in association with neuronal cell development as such markers for AD in the pre-plaque stage, female APP23 mice at eight, 19 and 31 weeks of age and corresponding control animals were tested for BPSD (elevated zero maze; sucrose preference test), motor coordination (rotarod), spatial memory and reversal learning (Morris water maze) and hippocampal neurogenesis as a neuronal correlate for hippocampus-dependent behavior. To evaluate a potential therapeutic effect of physical, cognitive and social stimulation, animals were exposed to environmental enrichment (EE) for one, twelve or 24 weeks from five weeks of age. In APP23, decreased anxiety accompanied increased agitation from eight weeks of age. Impairment of spatial memory and learning flexibility prior to plaque deposition involved an insufficient use of spatial search strategies associated with an unsuccessful compensatory increase of neurogenesis. EE had an overall beneficial effect on behavior and neurogenesis and thus constitutes a therapeutic tool to slow disease progression. BPSD, cognition and associated impaired neurogenesis complement clinical diagnostic markers for pre-plaque AD and contribute to an early detection essential to halt disease progression.

Introduction

With 24 million people affected worldwide, Alzheimer’s disease (AD) is the most prevalent form of dementia in patients over 65 years. Due to an aging society, the number of patients will even grow higher in the coming years [1,2]. However, the existing strategies to face this tremendous socio-economic challenge are insufficient. At present, no cure exists and available drugs merely slow down disease progression or attenuate its symptoms [3,4]. Histopathological alterations are detectable in post mortem brains years before any clinical symptoms occur [5]. To this date, an in vivo screening for AD is not available and existing biomarkers only confirm the disease when clinical symptoms are at hand. Consequently, patients are diagnosed and medicated long after the actual onset of AD when significant lesions of the brain are already present.

Initially, extracellular plaques containing amyloid-beta (Aß) [6,7] accumulate mainly in the hippocampus, an area highly involved in learning and memory processes [8]. These plaques potentially cause neuroinflammation, dysfunctional neurogenesis and subsequently neuronal cell loss [9,10]. During the course of the disease, plaques and neurodegeneration spread to the cortex and other brain regions and symptoms of dementia arise as clinical manifestation of a resulting severe brain atrophy. To prevent the invariably fatal disease progression in the future, diagnosis and treatment of AD at the earliest possible time-point are essential.

This goal appears to be in closer reach with the research focus shifting towards pathological processes in the brain preceding plaque deposition [5,13]. Several attempts have been made to establish biomarkers that help detecting AD at this early stage. Aß and tau as biomarkers both in plasma and cerebrospinal fluid are only sufficiently specific to confirm clinical AD. Neither imaging technique like structural and functional magnetic resonance imaging or positron-emission tomography could produce fully satisfying results detecting pre-plaque AD [2,14]. Thus, other more specific or complementary markers closely associated with early pathological processes are urgently required.

Symptoms of AD in humans not only include memory loss but also behavioral and psychological symptoms of dementia (BPSD) [1,15]. The successful reproduction of a variety of these symptoms prior to plaque deposition in AD mouse models [16] strongly implies that alterations in cognition and BPSD may serve as markers for early AD also in human patients. Neurogenesis appears to be altered in the hippocampus of transgenic mice not only during but also prior to plaque deposition [[17], [18], [19], [20]]. There is also evidence that adult neurogenesis is related to hippocampus-dependent behavior [21]. Therefore, a dysfunctional neurogenesis might be closely associated with the observed changes in cognition and BPSD. Examining this relation poses an important contribution to the better understanding of the relation between neuronal development and cognition or BPSD and is thus highly significant for the evaluation of behavioral markers as an early diagnostic tool.

Epidemiological studies in humans indicate that an active life decreases the risk for AD [22,23], promotes neuro-habilitation [24] and generally slows down age-dependent and AD-related cognitive decline [25,26]. Similarly, increased physical and social activity in an enriched environment (EE) ameliorated both BPSD and cognition in transgenic models of AD [[27], [28], [29]]. EE also proved to promote the survival of newborn neurons in the hippocampus of healthy adult mice [30,31]. It is very likely that such improvements, especially of hippocampal functions like spatial learning and memory, are closely associated with increased generation of new neurons [30,32,33]. They possibly constitute a cognitive reserve that contributes to the inhibition of AD [34]. In addition, EE has shown to decelerate the neurodegenerative process by activating microglia and preventing Aß-seeding in the plaque-stage of the disease [35]. Consequently, if implemented in time following the diagnosis of AD using adequately sensitive markers, EE as an activating therapy could help to inhibit or prevent the disease in the pre-plaque stage by increasing the cognitive reserve and activating microglia.

To obtain further understanding of the connection between neurogenesis and BPSD or cognition as potential early clinical diagnostic markers for AD, we examined different age-groups of the well-established APP23 AD mouse model [36] prior to plaque deposition at eight and 19 weeks and just after plaque onset at 31 weeks age. Together with age-matched, healthy wildtype animals they underwent tests for BPSD, motor coordination and cognitive function. Afterwards hippocampal neurogenesis and the presence of microglia were assessed using histological methods. To evaluate the potential beneficial effect of social and physical activity on AD, half of the animals were housed in environmentally enriched cages for the entire time of the study.

Section snippets

Animals

We used female transgenic APP23 mice (APP23) expressing human APP751 cDNA with the Swedish double mutation under the murine Thy-1.2 gene [36] (Novartis Pharma, Basel, Switzerland). Transgenic mice were bred based on a C57BL/6J background at Forschungseinrichtung für experimentelle Medizin (FEM) Berlin, Germany. Female age-matched C57BL/6J mice (Charles River Laboratories, Sulzfeld, Germany), served as wild type controls (WT). All animals entered the experiment at an age of five weeks and were

Exposure to EE reduces anxiety-related behavior of APP23 in the EZM

All animals were initially tested in the EZM to evaluate potential early signs of anxiety as a component of BPSD. Therefore, the following parameters were assessed: number of head dips, percentage time in the open quadrants, number of entries into the open quadrants and TbE.

The number of head dips as a parameter for anxiety [45] increased generally in EE (c: STD - EE; P < 0.001) and with advancing age (d: 1 W–24 W; P = 0.035). An effect of genotype could not be observed (g: WT - APP23; P = 0.284

Discussion

In the past years, research focus has shifted increasingly towards possible pathological processes in the brain that might actually be a priori responsible for the deposition of Aß plaques and AD in general [11,12]. In this context, the aim of our study was to find behavioral and histological markers that could serve as early predictors of AD. The well-established transgenic APP23 mouse [36] has proven to be a suitable model as it genetically develops amyloidosis and AD-like cognitive symptoms

Conclusion

Investigating the APP23 AD mouse model at eight, 19 and 31 weeks age, we detected uninhibited behavior at all ages in the EZM, reflecting a variety of BPSD as observed in AD patients, while mood and motor coordination were unaffected. The investigation of cognition confirmed the pre-plaque deficit of spatial memory and added strong evidence to both impaired learning flexibility and an insufficient use of hippocampal search strategies long before plaque deposition. The analysis of neurogenesis

Competing interest

The authors have declared that no competing interests exist.

Funding

This work was supported by Deutsche Forschungsgemeinschaft (STE 1450/8-1). A. Pfeffer was supported by Sonnenfeld Stiftung and Charité – Universitätsmedizin Berlin.

Acknowledgements

We thank Alexander Haake for excellent technical support.

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