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Alzheimer's disease (AD) has long been considered a brain-specific dementia syndrome. However, in recent decades, the occurrence of cardiovascular (CV) disease in the progression of AD has been confirmed by increasing epidemiological evidence. In this study, we conducted an in-depth cardiovascular characterization of a humanized amyloid precursor protein (APP) overexpressing mouse model (hAPP23 +/- ), which overexpresses the Swedish mutation (KM670/671NL). At the age of 6 mo, hAPP23 +/- mice had a lower survival, lower body weight, and increased corticosterone and VMA levels compared with C57BL/6 littermates. Systolic blood pressure was increased in hAPP23 +/- animals compared with C57BL/6 littermates, but diastolic blood pressure was not statistically different. Pulse pressure remained unchanged but abdominal and carotid pulse-wave velocity (aPWV and cPWV) were increased in hAPP23 +/- compared with C57BL/6 mice. Echocardiography showed no differences in systolic or diastolic cardiac function. Ex vivo evaluation of vascular function showed decreased adreno receptor dependent vasoconstriction of hAPP23 +/- aortic segments, although the isobaric biomechanics of the aortic wall were similar to C57BL/6 aortic segments. In conclusion, hAPP23 +/- mice exhibited high serum corticosterone levels, elevated systolic blood pressure, and increased arterial stiffness in vivo. However, ex vivo aortic stiffness of hAPP23 +/- aortic segments was not changed and vascular reactivity to α 1 -adrenoceptor stimulation was attenuated. These findings highlight the need for more frequent assessment of circulating stress hormone levels and PWV measurements in daily clinical practice for people at risk of AD. NEW & NOTEWORTHY We showed that male amyloid precursor protein (APP) transgenic mice have higher circulating stress hormone levels. As a result, higher systolic blood pressure and pulse-wave velocity were measured in vivo in addition to a smaller α-adrenergic receptor-dependent contraction upon ex vivo stimulation with phenylephrine. Our findings highlight the need for more frequent assessment of circulating stress hormone levels and PWV measurements in daily clinical practice for people at risk of Alzheimer's disease.

Aging is the key risk factor for Alzheimer's disease (AD). In addition, the amyloid-beta (Aβ) peptide is considered a critical neurotoxic agent in AD pathology. However, the connection between these factors is unclear. We aimed to provide an extensive characterization of the gene expression profiles of the amyloidosis APP23 model for AD and control mice and to evaluate the effect of aging on these profiles. We also correlated our findings to changes in soluble Aβ-levels and other pathological and symptomatic features of the model. We observed a clear biphasic expression profile. The first phase displayed a maturation profile, which resembled features found in young carriers of familial AD mutations. The second phase reflected aging processes and showed similarities to the progression of human AD pathology. During this phase, the model displayed a clear upregulation of microglial activation and lysosomal pathways and downregulation of neuron differentiation and axon guidance pathways. Interestingly, the changes in expression were all correlated to aging in general, but appeared more extensive/accelerated in APP23 mice., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Alzheimer's disease (AD), a neurodegenerative disorder, is characterized by the loss of neurons in specific regions of the CNS including the locus coeruleus (LC), the major noradrenergic locus in the CNS. Several animal models of AD have been developed that exhibit some of the pathophysiological changes in the CNS that are observed in AD patients. The purpose of this study was to determine if the integrity of the LC noradrenergic system is altered in the amyloid precursor protein 23 (APP23) mouse model of AD at the age of 3, 6 and 12 months through quantification of tyrosine hydroxylase (TH) mRNA expression. Despite a previous study suggesting alterations in the noradrenergic transmission system of APP23 mice, the current study failed to show altered TH-positive neuronal numbers or expression in LC noradrenergic neurons of APP23 mice versus wild-type (WT) littermates. However, the present study did demonstrate an age-dependent effect on TH mRNA expression. Both the number of TH-containing neurons and the amount of TH-positive grains/neuron significantly increased between the age of 3 and 6 months with no difference between 6 and 12 months. These observations indicate that any study comparing the noradrenergic system between WT (C57Bl/6) and experimental mice must strictly choose the age to be tested and limit age differences between control and experimental groups to the absolute minimum. More importantly, when long-term therapeutic interventions targeting the noradrenergic system are applied to mouse models, and related parameters are studied longitudinally, care should be taken to distinguish between potential therapeutic and strain-specific developmental or age-related alterations.

The APP23 model is a transgenic mouse model for Alzheimer's disease. Cognitive performance in the APP23-model was assessed by Morris Water Maze (MWM) and passive avoidance learning, but the latter failed to show any difference between the genotypes. In search of a non-spatial alternative for assessment of hippocampus-dependent memory, we evaluated an odour paired-associate test, which is based on learning an association between two sets of odours. The protocol includes a shaping phase, in which the animals learn to dig up a reward, a preliminary training phase and a training phase, where the actual association is learned. Subsequently, mice are tested for transitive inference and subjected to a symmetry test. Impairment was seen in the APP23 mice, in comparison with wild type mice, in training; however, both groups failed the transitivity and symmetry test. Possible explanations for this discrepancy with earlier published results are the advanced age of the mice or the C57Bl/6J background, in which the model was established.

Transgenic APP23 mice were generated to model Alzheimer's disease. The APP23 model develops pathological features, learning deficits, and memory deficits analogous to dementing patients. In this report, transgenic mice exhibited several behavioral disturbances indicating the presence of neuropsychiatric symptoms of dementia. Aiming to verify whether the model also develops other behavioral problems, the authors investigated ingestive behavior in APP23 males of 3, 6 and 12 months. In addition, body weights of a naive male group were longitudinally monitored starting at weaning. Olfactory acuity was evaluated in mice of different age groups. Although olfactory functioning of APP23 mice appeared intact, they drank more and took more food pellets compared with wild-type littermates during a 1-week registration period. From the age of 4.5 weeks onward, APP23 males weighed significantly less than their control littermates, whereas this difference became more prominent with increasing age. Our results suggest the presence of a hypermetabolic state in this model. This is the first report, evidencing the presence of changes in eating and drinking behavior in a single transgenic Alzheimer mouse model., ((Copyright) 2008 APA, all rights reserved.)

Rationale: The interest for acetylcholinesterase inhibitors in the treatment of Alzheimer's disease has been greatly renewed owing to the discovery of a broad range of additional cholinergic and non-cholinergic effects, exploitable to maximize the efficacy of these drugs beyond merely improving intellectual functions at the symptomatic level., Objectives: The age-dependent cognitive decline in the valid APP23 transgenic mouse model for Alzheimer's disease was employed to evaluate disease-modifying efficacy of chronic treatment with donepezil., Materials and Methods: At age 6 weeks, heterozygous APP23 mice and control littermates were subcutaneously implanted with osmotic pumps delivering saline or donepezil (0.27 or 0.58 mg/kg per day). After 2 months of treatment, a 3-week wash-out period was allowed to prevent bias from sustained symptomatic effects before cognitive evaluation in the Morris water maze commenced., Results: Donepezil (0.27 mg/kg per day)-treated APP23 mice performed significantly better than their sham-treated counterparts during the Morris water maze acquisition phase and the subsequent probe or retention trial. Chronic donepezil (0.27 mg/kg per day) treatment improved spatial accuracy in APP23 mice as to reach the same level of performance as wild-type control animals on this complex visual-spatial learning task., Conclusion: This is the first study reporting disease-modifying efficacy of donepezil at the level of cognitive performance in transgenic mice modeling Alzheimer's disease.

Transgenic mouse models of Alzheimer's disease (AD) expressing high levels of amyloid precursor protein (APP) with familial AD (FAD) mutations have proven to be extremely useful in understanding pathogenic processes of AD especially those that involve amyloidogenesis. We earlier described Austrian APP T714I pathology that leads to one of the earliest AD age-at-onsets with abundant intracellular and extracellular amyloid deposits in brain. The latter strikingly was non-fibrillar diffuse amyloid, composed of N-truncated A beta 42 in absence of A beta 40. In vitro, this mutation leads to one of the highest A beta 42/A beta 40 ratios among all FAD mutations. We generated an APP T714I transgenic mouse model that despite having 10 times lower transgene than endogenous murine APP deposited intraneuronal A beta in brain by 6 months of age. Accumulations increased with age, and this was paralleled by decreased brain sizes on volumetric MRI, compared to age-matched and similar transgene-expressing APP wild-type mice, although, with these levels of transgenic expression we did not detect neuronal loss or significant memory impairment. Immunohistochemical studies revealed that the majority of the intraneuronal A beta deposits colocalized with late endosomal markers, although some A beta inclusions were also positive for lysosomal and Golgi markers. These data support earlier observations of A beta accumulation in the endosomal-lysosomal pathway and the hypothesis that intraneuronal accumulation of A beta could be an important factor in the AD pathogenesis.

Valid animal models are indispensable in the drug discovery pipeline for dementia. Transgenic APP23 mice model Alzheimer's disease patients' memory deficits and additionally present with various behavioural disturbances, such as aggressive behaviour. The present study investigated and confirmed significant sensitivity of the model to the aggression-lowering ability of the antipsychotic agent risperidone (CAS 106266-06-2). The sensitivity for such anti-aggressive action contributes to the therapeutic predictive validity of the APP23 model of Alzheimer's disease, which can be used as a pre-clinical screening tool for the identification of novel anti-aggressive agents.

Alzheimer's disease is characterised by both cognitive deterioration and the development of a wide range of neuropsychiatric disturbances, among which affective disturbances, stereotyped behaviour, dietary hyperactivity and changes in sexual behaviour. The transgenic APP23 mouse models Alzheimer's disease and has shown to be a unique tool in the study of this condition. APP23 mice develop, next to the age-dependent cognitive decline, also a range of behavioural problems, such as circadian activity disturbances and increased aggression, in analogy with the dementing patients. The present study aimed to investigate whether this model also develops mood disturbances and changes in sexual behaviour. Using two behavioural despair paradigms and the sucrose preference test, we did not find evidence for the development of depression-related behaviours. A sophisticated protocol was neither able to unravel changes in male sexual behaviour between APP23 and WT mice. The present study nevertheless provides evidence that the APP23 mice are more anxious and fearful in comparison with control littermates, which opens perspectives to future treatment studies.

In addition to cognitive deterioration, Alzheimer's disease patients exhibit behavioral and psychological signs and symptoms of dementia. Behavioral alterations are a major source of caregiver stress and an important contributor in the decision to institutionalize patients. The amyloid precursor protein (APP) 23 transgenic mouse model develops amyloid plaques from the age of 6 months onward and exhibits tau pathology, which is absent in most other amyloid-based models. Besides mimicking the demented patients' memory deficits, these transgenic mice present with various behavioral disturbances, thereby approximating the clinical situation remarkably well. Using an isolation-induced/resident-intruder paradigm of aggression, the authors revealed increased aggressiveness in male APP23 mice at the ages of 6 and 12 months. The presence of aggressive disturbances in this valuable mouse model opens perspectives to evaluate aggression-modulating therapies., (2006 APA, all rights reserved)

Alzheimer's disease (AD) patients typically present short-term memory deficits, before long-term memory capacity declines with disease progression. Several studies have described learning and memory deficits in the APP23 mouse model. Our group reported a decline of learning and memory capacities from the age of 3 months onwards using a hidden-platform Morris water maze (MWM). The aim of the present study was to evaluate working and reference memory in APP23 mice in the same plus-shaped water maze. The transgenic mice had slower learning curves; however, consolidation of the learned information appeared intact in this learning paradigm. This report demonstrates impairment of working memory in this transgenic Alzheimer model.

Two transgenic mouse models expressing mutated human amyloid precursor protein and previously found to display cognitive and behavioural alterations, reminiscent of Alzheimer patients' symptomatology, were scrutinised for putative brain region-specific changes in neurochemical parameters. Brains of NSE-hAPP751m-57, APP23 and wild-type mice were microdissected to perform brain region-specific neurochemical analyses. Impairment of cholinergic transmission, the prominent neurochemical deficit in Alzheimer brain, was examined; acetylcholinesterase and choline acetyltransferase activity levels were determined as markers of the cholinergic system. Since Alzheimer neurodegeneration is not restricted to the cholinergic system, brain levels of biogenic amines and metabolites, and amino acidergic neurotransmitters and systemic amino acids were analysed as well. Cholinergic dysfunction, reflected in reduced enzymatic activity in the basal forebrain nuclei, was restricted to the APP23 model, which also exhibited more outspoken and more widespread changes in other neurotransmitter systems. Significant changes in compounds of the noradrenergic and serotonergic system were observed, as well as alterations in levels of the inhibitory neurotransmitter glycine and systemic amino acids. These observations were clearly in occurrence with the more pronounced histopathological and behavioural phenotype of the APP23 model. As transgenic models often do not represent an end-stage of the disease, some discrepancies with results from post-mortem human Alzheimer brain analyses were apparent; in particular, no significant alterations in excitatory amino acid levels were detected. Our findings of brain region-specific alterations in compound levels indicate disturbed neurotransmission pathways, and greatly add to the validity of APP23 mice as a model for Alzheimer's disease. Transgenic mouse models may be employed as a tool to study early-stage neurochemical changes, which are often not accessible in Alzheimer brain., ((c) 2005 Elsevier Ltd. All rights reserved.)

Over the past decade, clinical Alzheimer's disease research has been challenged with an increased interest in noncognitive symptomatology, commonly referred to as behavioural and psychological signs and symptoms of dementia (BPSD). In accordance, major attention is being paid to behavioural alterations in the phenotyping of transgenic mouse models. Besides an age-dependent decline of cognitive functions, the APP23 model was previously shown to exhibit cage activity disturbances, reminiscent of diurnal rhythm disturbances in Alzheimer patients. To further scrutinize these observations, circadian patterns of horizontal locomotor activity were assessed in 3-, 6- and 12-month-old APP23 mice and wild-type littermates in a test paradigm continuously recording cage activity over a period ranging from 1 to 3 days. At the age of 3 months, APP23 profiles resembled the wild-type pattern to a large extent, although minor differences were already noticeable. Six-month-old APP23 mice displayed an altered activity profile with a first indication of increased activity during the second half of the active phase, reminiscent of sundowning behaviour in Alzheimer patients. This bimodal overnight activity pattern became even more evident at the age of 12 months. The APP23 model was therefore shown to display an age-dependent development of cage activity disturbances and sundowning-like behaviour. A comparison is made with actigraphic recordings of human Alzheimer patients exhibiting sundowning behaviour. This first report of diurnal rhythm disturbances and sundowning-like phenomena in a transgenic mouse model greatly adds to the validity of the APP23 model.

Heterozygous APP23 mice, expressing human amyloid-precursor protein with the Swedish double mutation and control littermates, were subjected to behavioral and neuromotor tasks at the age of 6-8 weeks, 3 and 6 months. A hidden-platform Morris-type water maze showed an age-dependent decline of spatial memory capacities in the APP23 model. From the age of 3 months onwards, the APP23 mice displayed major learning and memory deficits as demonstrated by severely impaired learning curves during acquisition and impaired probe trial performance. In addition to the cognitive deficit, APP23 mice displayed disturbed activity patterns. Overnight cage-activity recording showed hyperactivity in the transgenics for the three age groups tested. However, a short 2-h recording during dusk phase demonstrated lower activity levels in 6-month-old APP23 mice as compared to controls. Moreover, at this age, APP23 mice differed from control littermates in exploration and activity levels in the open-field paradigm. These findings are reminiscent of disturbances in circadian rhythms and activity observed in Alzheimer patients. Determination of plaque-associated human amyloid-beta 1-42 peptides in brain revealed a fivefold increase in heterozygous APP23 mice at 6 months as compared to younger transgenics. This increase coincided with the first appearance of plaques in hippocampus and neocortex. Spatial memory deficits preceded plaque formation and increase in plaque-associated amyloid-beta 1-42 peptides, but probe trial performance did correlate negatively with soluble amyloid-beta brain concentration in 3-month-old APP23 mutants. Detectable plaque formation is not the (only) causal factor contributing to memory defects in the APP23 model.