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
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.
References (102)
- et al.
Alzheimer disease: epidemiology, diagnostic criteria, risk factors and biomarkers
Biochem. Pharmacol.
(2014) Alzheimer's disease and amyloid: culprit or coincidence?
Int. Rev. Neurobiol.
(2012)Long-lasting impairment in hippocampal neurogenesis associated with amyloid deposition in a knock-in mouse model of familial Alzheimer’s disease
Exp. Neurol.
(2007)- et al.
Environment as 'Brain Training': a review of geographical and physical environmental influences on cognitive ageing
Ageing Res. Rev.
(2015) Effects of environmental enrichment on exploration, anxiety, and memory in female TgCRND8 Alzheimer mice
Behav. Brain Res.
(2008)Enrichment improves cognition in AD mice by amyloid-related and unrelated mechanisms
Neurobiol. Aging
(2007)Cognitive and physical activity differently modulate disease progression in the amyloid precursor protein (APP)-23 model of Alzheimer’s disease
Biol. Psychiatry
(2006)Behavioral phenotyping strategies for mutant mice
Neuron
(2008)Mood and male sexual behaviour in the APP23 model of Alzheimer’s disease
Behav. Brain Res.
(2007)Spatial learning, exploration, anxiety, and motor coordination in female APP23 transgenic mice with the Swedish mutation
Brain Res.
(2002)
Comparison of the elevated plus and elevated zero mazes in treated and untreated male Sprague-Dawley rats: effects of anxiolytic and anxiogenic agents
Pharmacol. Biochem. Behav.
Individual housing and handling procedures modify anxiety levels of Tg2576 mice assessed in the zero maze test
Physiol. Behav.
Anxiety, defence and the elevated plus-maze
Neurosci. Biobehav. Rev.
Antidepressant-like effect of Butea superba in mice exposed to chronic mild stress and its possible mechanism of action
J. Ethnopharmacol.
Behavioral phenotyping of mice in pharmacological and toxicological research
Exp. Toxicol. Pathol.
Milestones of neuronal development in the adult hippocampus
Trends Neurosci.
Aspects of spatial memory and behavioral disinhibition in Tg2576 transgenic mice as a model of Alzheimer’s disease
Behav. Brain Res.
Lifelong immunization with human beta-amyloid (1-42) protects Alzheimer’s transgenic mice against cognitive impairment throughout aging
Neuroscience
Environmental enrichment alters plus maze, but not maternal defense performance in mice
Physiol. Behav.
At the interface of sensory and motor dysfunctions and Alzheimer’s disease
Alzheimers Dement
Progressive age-related impairment of cognitive behavior in APP23 transgenic mice
Neurobiol. Aging
Morris water maze search strategy analysis in PDAPP mice before and after experimental traumatic brain injury
Exp. Neurol.
The neurogenic reserve hypothesis: what is adult hippocampal neurogenesis good for?
Trends Neurosci.
Late age increase in soluble amyloid-beta levels in the APP23 mouse model despite steady-state levels of amyloid-beta-producing proteins
Biochim. Biophys. Acta
Role of pro-inflammatory cytokines released from microglia in Alzheimer’s disease
Ann. Transl. Med.
Neurogenesis and alterations of neural stem cells in mouse models of cerebral amyloidosis
Am. J. Pathol.
Environmental enrichment restores neurogenesis and rapid acquisition in aged rats
Neurobiol. Aging
Independent effects of intra- and extracellular Abeta on learning-related gene expression
Am. J. Pathol.
Alzheimer’s disease facts and figures
Alzheimers Dement
Current and future treatments for Alzheimer’s disease
Ther. Adv. Neurol. Disord.
100 years and counting: prospects for defeating Alzheimer's disease
Science
Multimodal techniques for diagnosis and prognosis of Alzheimer’s disease
Nature
The precursor of Alzheimer’s disease amyloid A4 protein resembles a cell-surface receptor
Nature
Amyloid plaque core protein in Alzheimer disease and down syndrome
Proc. Natl. Acad. Sci. U. S. A.
Staging of Alzheimer-related cortical destruction
Eur. Neurol.
Alzheimer's disease: genes, proteins, and therapy
Physiol. Rev.
Adult hippocampal neurogenesis and its role in Alzheimer’s disease
Mol. Neurodegener.
Stop Alzheimer’s before it starts
Nature
Inconsistencies and controversies surrounding the amyloid hypothesis of Alzheimer’s disease
Acta Neuropathol. Commun.
Biomarkers for preclinical Alzheimer’s disease
J. Alzheimers Dis.
Behavioral and psychological symptoms of dementia characteristic of mild Alzheimer patients
Psychiatry Clin. Neurosci.
Using mice to model Alzheimer's dementia: an overview of the clinical disease and the preclinical behavioral changes in 10 mouse models
Front. Genet.
Decreased adult hippocampal neurogenesis in the PDAPP mouse model of Alzheimer’s disease
J. Comp. Neurol
Impaired neurogenesis is an early event in the etiology of familial Alzheimer’s disease in transgenic mice
J. Neurosci. Res.
Early changes in hippocampal neurogenesis in transgenic mouse models for Alzheimer’s disease
Mol. Neurobiol.
Why new neurons? Possible functions for adult hippocampal neurogenesis
J. Neurosci.
Cardiovascular fitness, cortical plasticity, and aging
Proc. Natl. Acad. Sci. U. S. A.
Participation in cognitively stimulating activities and risk of incident Alzheimer disease
JAMA
An enriched environmental programme during inpatient neuro-rehabilitation: A randomized controlled trial
J. Rehabil. Med.
Impoverished environment, cognition, aging and dementia
Rev. Neurosci.
Cited by (16)
Environmental enrichment improves cognitive function, learning, memory and anxiety-related behaviours in rodent models of dementia: Implications for future study
2024, Neurobiology of Learning and MemoryApathy-like behaviour in tau mouse models of Alzheimer's disease and frontotemporal dementia
2024, Behavioural Brain ResearchReduction of restricted repetitive behavior by environmental enrichment: Potential neurobiological mechanisms
2023, Neuroscience and Biobehavioral ReviewsPrenatal LPS exposure increases hippocampus IL-10 and prevents short-term memory loss in the male adolescent offspring of high-fat diet fed dams
2022, Physiology and BehaviorCitation Excerpt :The findings of this study can be used in the future to better understand the impacts of insults in the periods of gestation and lactation in the development of neuropsychiatric or cognitive diseases. Moreover, since impaired memory and neurochemical alterations developed during children and adolescents phases may contribute to the development of Alzheimer's and other cognitive diseases in later life [5, 90, 95, 136], studies involving tolerance with TRL4 agonists during these phases may decrease the progression or impact of these diseases [50, 128]. In addition, the model proposed in the present study may promote discussions in terms of clinical implications, as well as guide future studies for interventions to be done at early ages to prevent diseases related to the concept of DOHaD.
Behavioural and psychological symptoms of dementia in mouse models of Alzheimer's disease-related pathology
2020, Neuroscience and Biobehavioral ReviewsCitation Excerpt :These tasks have been shown to be sensitive to anti-depressants (Crowley et al., 2004), with longer periods of immobility indicating higher levels of depressive-like behaviours. Anhedonia is the inability to find pleasure in a normally pleasurable stimulus, and can be measured in mice by quantifying sucrose consumption (Pfeffer et al., 2018). Experiments investigating depressive-like behaviours in amyloidogenic and tauogenic mouse models suggest that behavioural despair and anhedonia increases with progressive AD-related pathology (see Table 5).