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Due to global population growth, age-related disorders like cardiovascular disease and dementia are anticipated to increase. Recent data suggests a connection between cardiovascular disease and neurodegeneration, especially focusing on arterial stiffness (AS) and Alzheimer's disease (AD). In light of this, we conducted a study to explore the impact of long-term nitric oxide synthase (NOS) isoform inhibition, which leads to AS, on neurobehavioral performance. We also compared these effects in an AD model and control mice. C57BL/6 and hAPP23+/− mice (an established AD model) were given 0.5 mg/mL N(G)-Nitro-L-Arginine Methyl Ester (L-NAME) in their drinking water for 16 weeks. Our findings indicate that chronic non-selective NOS inhibition increased AS and reduced spatiotemporal learning and memory in both C57BL/6 and hAPP23+/− mice. These effects were consistent across both groups, emphasizing the role of neuronal NOS (nNOS) in cognitive aging, regardless of genetic predisposition to AD. [ABSTRACT FROM AUTHOR]

Simple Summary: The tau protein normally functions to maintain the stability of microtubules, the cellular cytoskeleton that provides structure and shape to eukaryotic cells. Tau protein malfunction is a core feature of a group of neurodegenerative diseases labeled 'tauopathies' that include, among others, Alzheimer's disease and frontotemporal dementia, with parkinsonism linked to chromosome 17 (FTDP-17). In these disorders, abnormally hyperphosphorylated tau is accumulated in intraneuronal tangles, disturbing normal cellular function and acting as the basis of neurofibrillary degeneration and dementia. FTDP-17 is indeed a form of frontotemporal dementia or frontotemporal degeneration characterized by a loss of nerve cells in areas of the brain called the frontal and temporal lobes. Over time, this cell loss affects personality, behavior, language, and movement. Valid animal models are vital to enhance our understanding of molecular disease mechanisms and as preclinical tools to identify novel treatment targets and to screen the efficacy of novel drug candidates or other therapeutic approaches. We report the validity of two genetically modified mouse models that express a mutated form of human tau protein associated with FTDP-17. With aging, both lines developed progressively worsening tau-related pathology, cognitive decline, and behavioral changes reminiscent of the symptom profile of FTDP-17 patients. Background: The Tau58/2 and Tau58/4 mouse lines expressing 0N4R tau with a P301S mutation mimic aspects of frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). In a side-by-side comparison, we report the age-dependent development of cognitive, motor, and behavioral deficits in comparison with the spatial-temporal evolution of cellular tau pathology in both models. Methods: We applied the SHIRPA primary screen and specific neuromotor, behavioral, and cognitive paradigms. The spatiotemporal development of tau pathology was investigated immunohistochemically. Levels of sarkosyl-insoluble paired helical filaments were determined via a MesoScale Discovery biomarker assay. Results: Neuromotor impairments developed from age 3 months in both models. On electron microscopy, spinal cord neurofibrillary pathology was visible in mice aged 3 months; however, AT8 immunoreactivity was not yet observed in Tau58/4 mice. Behavioral abnormalities and memory deficits occurred at a later stage (>9 months) when tau pathology was fully disseminated throughout the brain. Spatiotemporally, tau pathology spread from the spinal cord via the midbrain to the frontal cortex, while the hippocampus was relatively spared, thus explaining the late onset of cognitive deficits. Conclusions: Our findings indicate the face and construct validity of both Tau58 models, which may provide new, valuable insights into the pathologic effects of tau species in vivo and may consequently facilitate the development of new therapeutic targets to delay or halt neurodegenerative processes occurring in tauopathies. [ABSTRACT FROM AUTHOR]

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 α1-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. [ABSTRACT FROM AUTHOR]

Although neuroglobin confers neuroprotection against Alzheimer's disease ( AD) pathology, its expression becomes downregulated in late-stage AD. Here, we provide evidence that indicates that this decrease is associated with the AD-linked angiopathy. While wild-type mice of different ages show upregulated cerebral neuroglobin expression upon whole-body hypoxia, APP23 mice exhibit decreased cerebral transcription of neuroglobin. Interestingly, transcription of cytoglobin, whose involvement in amyloid pathology still needs to be elucidated, follows a similar pattern. To further unravel the underlying mechanism, we examined the expression levels of the RE-1-silencing transcription factor ( REST/ NRSF) after identifying a recognition site for it in the regulatory region of both globins. Neuroglobin-cytoglobin- REST/ NRSF expression correlations are detected mainly in the cortex. This raises the possibility of REST/ NRSF being an upstream regulator of these globins. [ABSTRACT FROM AUTHOR]

Apolipoprotein E deficient (ApoE −/− ) mice with a heterozygous mutation in the fibrillin-1 gene (Fbn1 C1039G +/− ) show spontaneous atherosclerotic plaque ruptures, disturbances in cerebral flow and sudden death when fed a Western-type diet (WD). The present study focused on motor coordination and spatial learning of ApoE −/− Fbn1 C1039G +/− mice on WD for 20 weeks ( n = 21). ApoE −/− mice on WD ( n = 24) and ApoE −/− Fbn1 C1039G +/− mice on normal diet (ND, n = 21) served as controls. Starting from 10 weeks of diet, coordination was assessed every two weeks by the following tests: gait analysis, stationary beam, wire suspension and accelerating rotarod. The Morris water maze test was performed after 13 weeks of diet to study spatial learning. At the end of the experiment (20 weeks of WD), the mice were sacrificed and the brachiocephalic artery and brain were isolated. From 12 weeks onward, gait analysis of ApoE −/− Fbn1 C1039G +/− mice on WD revealed a progressive increase in track width as compared to ApoE −/− mice on WD and ApoE −/− Fbn1 C1039G +/− mice on ND (at 20 weeks: 29.8 ± 0.6 mm vs. 25.8 ± 0.4 mm and 26.0 ± 0.5 mm). Moreover, the stationary beam test showed a decrease in motor coordination of ApoE −/− Fbn1 C1039G +/− mice on WD at 18 and 20 weeks. The wire suspension test and accelerating rotarod could not detect signs of motor impairment. Spatial learning was also not affected. Histological analysis of the brachiocephalic artery showed larger and more stenotic plaques in ApoE −/− Fbn1 C1039G +/− mice on WD. Furthermore, the parietal cortex of ApoE −/− Fbn1 C1039G +/− mice on WD showed pyknotic nuclei as a sign of hypoxia and the percentage of pyknosis correlated with track width. In conclusion, gait analysis may be an efficient method for analyzing hypoxic brain damage in the ApoE −/− Fbn1 C1039G +/− mouse model. This test could be of value to assess the effect of potential anti-atherosclerotic therapies in mice. [ABSTRACT FROM AUTHOR]

Abstract: Neuroglobin (Ngb), a neuron-specific heme-binding protein that binds O2, CO and NO reversibly, and promotes in vivo and in vitro cell survival after hypoxic and ischaemic insult. Although the mechanisms of this neuroprotection remain unknown, Ngb might play an important role in counteracting the adverse effects of ischaemic stroke and cerebral hypoxia. Several Ngb overexpressing mouse models have confirmed this hypothesis; however, these models were not yet exposed to in-depth behavioural characterisations. To investigate the potential changes in behaviour due to Ngb overexpression, heterozygous mice and wild type (WT) littermates were subjected to a series of cognitive and behavioural tests (i.e., the SHIRPA primary screening, the hidden-platform Morris water maze, passive avoidance learning, 47h cage activity, open field exploration, a dark–light transition box, an accelerating rotarod, a stationary beam, a wire suspension task and a gait test) under normoxic and hypoxic conditions. No significant behavioural differences were found between WT and Ngb-overexpressing mice at three months old. However, one-year-old Ngb-overexpressing mice travelled more distance on the stationary beam compared with WT littermates. This result shows that the constitutive overexpression of Ngb might counteract the endogenous decrease of Ngb in crucial brain regions such as the cerebellum, thereby counteracting age-induced neuromotor dysfunction. This article is part of a Special Issue entitled: Oxygen Binding and Sensing Proteins. [Copyright &y& Elsevier]

Increasing epidemiological and experimental evidence points to a link between arterial stiffness and rapid cognitive decline. However, the underlying mechanism linking the two diseases is still unknown. The importance of nitric oxide synthases in both diseases is well-defined. In this study, we introduced arterial stiffness in both genetic (eNOS−/−, endothelial nitric oxide synthase knockout) and pharmacological (N(G)-nitro-L-arginine methyl ester (L-NAME) treatment) NO dysfunction models to study their association with cognitive decline. Our findings demonstrate that the non-selective inhibition of NOS activity with L-NAME induces cardiac dysfunction, arterial stiffness, and a decline in hippocampal-dependent learning and memory. This outcome demonstrates the importance of neuronal NOS (nNOS) in both cardiovascular and neurological pathophysiology and its potential contribution in the convergence between arterial stiffness and cognitive decline. [ABSTRACT FROM AUTHOR]

Increasing epidemiological evidence highlights the association between systemic insulin resistance and Alzheimer's disease (AD). As insulin resistance can be caused by high-stress hormone levels and since hypercortisolism appears to be an important risk factor of AD, we aimed to investigate the systemic insulin functionality and circulating stress hormone levels in a mutant humanized amyloid precursor protein (APP) overexpressing (hAPP23+/−) AD mouse model. Memory and spatial learning of male hAPP23+/− and C57BL/6 (wild type, WT) mice were assessed by a Morris Water Maze (MWM) test at the age of 4 and 12 months. The systemic metabolism was examined by intraperitoneal glucose and insulin tolerance tests (GTT, ITT). Insulin and corticosterone levels were determined in serum. In the hippocampus, parietal and occipital cortex of hAPP23+/− brains, amyloid-beta (Aβ) deposits were present at 12 months of age. MWM demonstrated a cognitive decline in hAPP23+/− mice at 12 but not at 4 months, evidenced by increasing total path lengths and deteriorating probe trials compared to WT mice. hAPP23+/− animals presented increased serum corticosterone levels compared to WT mice at both 4 and 12 months. hAPP23+/− mice exhibited peripheral insulin resistance compared to WT mice at 4 months, which stabilized at 12 months of age. Serum insulin levels were similar between genotypes at 4 months of age but were significantly higher in hAPP23+/− mice at 12 months of age. Peripheral glucose homeostasis remained unchanged. These results indicate that peripheral insulin resistance combined with elevated circulating stress hormone levels could be potential biomarkers of the pre-symptomatic phase of AD. [ABSTRACT FROM AUTHOR]

Abstract: Molecular and electrophysiological studies have provided evidence for a general downregulation of the GABAergic system in the Fmr1 knockout mouse. GABAA receptors are the main inhibitory receptors in the brain and the GABAA receptor was proposed as a novel target for treatment of the fragile X syndrome, the most frequent form of intellectual disability. This study examined the functionality of the GABAA receptor in rotarod and elevated plus maze tests with fragile X mice treated with GABAA receptor agonists, the benzodiazepine diazepam and the neuroactive steroid alphaxalone. In addition, the effect of GABAA receptor activation on the audiogenic seizure activity was determined. We proved that the GABAA receptor is still sensitive to GABAergic drugs as the sedative effect of diazepam resulted in a decreased latency time on the rotarod and alphaxalone had a clear anxiolytic effect in the elevated plus maze, decreasing the frequency of entries, the total time spent and the path length in the closed arms. We also observed that treatment with ganaxolone could rescue audiogenic seizures in Fmr1 knockout mice. These findings support the hypothesis that the GABAA receptor is a potential therapeutic target for fragile X syndrome. [Copyright &y& Elsevier]

Altered concentrations of monoamine neurotransmitters and metabolites have been repeatedly found in people with Down syndrome (DS, trisomy 21). Because of the limited availability of human post-mortem tissue, DS mouse models are of great interest to study these changes and the underlying neurobiological mechanisms. Although previous studies have shown the potential of Ts65Dn mice – the most widely used mouse model of DS – to model noradrenergic changes, a comprehensive monoaminergic characterization in multiple brain regions has not been performed so far. Here, we used RP-HPLC with electrochemical detection to quantify (nor)adrenergic (NA, adrenaline and MHPG), dopaminergic (DA, HVA and DOPAC), and serotonergic compounds (tryptophan, 5-HT and 5-HIAA) in ten regionally dissected brain regions of Ts65Dn mice, as well as in Dp1Tyb mice – a novel DS mouse model. Comparing young adult aneuploid mice (2.5–5.5 months) with their euploid WT littermates did not reveal generalized monoaminergic dysregulation, indicating that the genetic overload in these mice barely affected the absolute concentrations at this age. Moreover, we studied the effect of aging in Ts65Dn mice: comparing aged animals (12–13 months) with their younger counterparts revealed a large number of significant changes. In general, the (nor)adrenergic system appeared to be reduced, while serotonergic compounds were increased with aging. Dopaminergic alterations were less consistent. These overall patterns appeared to be relatively similar for Ts65Dn and WT mice, though more observed changes were regarded significant for WT mice. Similar human post-mortem studies are necessary to validate the monoaminergic construct validity of the Ts65Dn and Dp1Typ mouse models. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Introduction The cholinergic system is involved in learning and memory and is affected in neurodegenerative disorders such as Alzheimer's disease. The possibility of non-invasively detecting alterations of neurotransmitter systems in the mouse brain would greatly improve early diagnosis and treatment strategies. The hypothesis of this study is that acute modulation of the cholinergic system might be reflected as altered functional connectivity (FC) and can be measured using pharmacological resting-state functional MRI (rsfMRI). Material and methods Pharmacological rsfMRI was performed on a 9.4 T MRI scanner (Bruker BioSpec, Germany) using a gradient echo EPI sequence. All mice were sedated with medetomidine. C57BL/6 mice ( N = 15/group) were injected with either saline, the cholinergic antagonist scopolamine, or methyl-scopolamine, after which rsfMRI was acquired. For an additional group ( N = 8), rsfMRI scans of the same mouse were acquired first at baseline, then after the administration of scopolamine and finally after the additional injection of the cholinergic agonist milameline. Contextual memory was evaluated with the same setup as the pharmacological rsfMRI using the passive avoidance behavior test. Results Scopolamine induced a dose-dependent decrease of FC between brain regions involved in memory. Scopolamine-induced FC deficits could be recovered completely by milameline for FC between the hippocampus–thalamus, cingulate–retrosplenial, and visual–retrosplenial cortex. FC between the cingulate–rhinal, cingulate–visual and visual–rhinal cortex could not be completely recovered by milameline. This is consistent with the behavioral outcome, where milameline only partially recovered scopolamine-induced contextual memory deficits. Methyl-scopolamine administered at the same dose as scopolamine did not affect FC in the brain. Conclusion The results of the current study are important for future studies in mouse models of neurodegenerative disorders, where pharmacological rsfMRI may possibly be used as a non-invasive read-out tool to detect alterations of neurotransmitter systems induced by pathology or treatment. [ABSTRACT FROM AUTHOR]

During the last decades, most of the preclinical neurodegenerative research was performed in mouse models of amyloidosis, tauopathies or α-synucleinopathies preferentially maintained on a C57BL/6J background. However, comprehensive neurobehavioural data from C57BL/6J mice outlining the critical point of spontaneous cognitive decline are incomplete. In this study, we aimed for the neurobehavioural phenotyping of hippocampus-dependent spatial learning and memory of aging C57BL/6J mice. Neurobehavioural phenotyping was performed by means of a Morris Water Maze (MWM) and a Novel Object Recognition (NOR) test. MWM measurements revealed signs of age-related memory loss in C57BL/6J animals from the age of 6 months onward. The NOR assessment strengthened latter finding by decreasing discrimination indexes (DI) and recognition indexes (RI) starting from the age of 6 months. Taken together, these findings contribute to the current knowledge of spontaneous cognitive behaviours of this perhaps most widely used mouse strain and serve as a benchmark for dementia mouse models to distinguish spontaneous from pathological neurodegenerative behaviour. • C57BL/6J mice show spontaneous cognitive decline from an adult age onward. • C57BL/6J mice show deteriorating visuospatial learning and memory with age. • C57BL/6J mice show deteriorating recognition memory with age. [ABSTRACT FROM AUTHOR]

Abstract: The peptidome encompasses all the peptides present in a particular cell, tissue or organism at a particular point in time. Neuropeptidomics studies the peptidome of the nervous system and will become increasingly important in neuroscience research. Novel peptides can be discovered and, when applied to disease models, key players in pathophysiological mechanisms will be identified. That way, they can serve as drug targets or biomarkers. Presently, different extraction protocols are in use, but no consensus has been reached on what fixation and extraction protocol is best suited for brain tissue. Therefore, in this article we compare different methods for quenching of proteolytic activity (snap-freezing of whole mouse in liquid nitrogen immediately after cervical dislocation, freezing of the dissected brain in 2-methyl-butane and heat denaturation of the tissue by microwave treatment) in combination with different extraction methods. The protocol that combines submersion in liquid nitrogen with extraction in 0.25% acetic acid results in the highest number of unique identifications, a high conservation of posttranslational modifications, the best reproducibility between duplicate samples and the best comparison with former studies on mouse brain peptides. For these reasons, we recommend the use of this protocol in future neuropeptidomics studies. [Copyright &y& Elsevier]