Reduction in open field activity in the absence of memory deficits in the AppNL−G−F knock-in mouse model of Alzheimer’s disease

Whyte, Lauren S.; Hemsley, Kim M.; Lau, Adeline A.; Hassiotis, Sofia; Saito, Takashi; Saido, Takaomi C.; Hopwood, John J.; Sargeant, Timothy J.

doi:10.1016/j.bbr.2017.09.006

Cited by 52 publications

(66 citation statements)

References 21 publications

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“…Therefore, early behavioral impairments observed in such transgenic mice might be induced by the interaction of overexpressed APP with a variety of molecular substrates, and not by AD pathology proper. However as it turned-out, APP NL-G-F mice appeared to display a relatively mild behavioral phenotype, in accordance with previous reports, which becomes more manifest at a relatively advanced age [7,8].…”

Section: Discussionsupporting

confidence: 91%

“…This marginal effect during the reversal retention test could be due to somewhat more variable performance in the APP NL-G-F group, and not necessary to a robust cognitive defect as such. In effect, a previous report failed to show early cognitive defects in these mice [8], and in our report, at 10-11 months of age ( Figure 6C), no differences were observed, neither in reversal learning, nor in probe trial performance. We cannot exclude that more challenging testing might still reveal the robust occurrence of early cognitive changes in these mice.…”

Section: Spatial Reversal Learning Defect In App Nl-g-f Micesupporting

confidence: 49%

“…Models that endogenously overproduce Aβ42 without overexpressing APP have been generated by knock-in (KI) of a humanized Aβ sequence [7]. Characterization of the functional consequences of the KI strategy on complex behavioral and cognitive abilities and brain circuitry is still limited, and previous reports showed only mild behavioral defects at the age examined in the present report [8].…”

Section: Introductionmentioning

confidence: 81%

“…In the current study, we compared APP NL-F/NL-F knock-in mice with high Aβ42/40 ratio to APP NL/NL mice 60 at two time points that reflect early pathological stages, i.e. before and at the initial stage of plaque 61 deposition 8 . Different aspects of spatial learning and memory were assessed using an extended 62 protocol in the Morris water maze task to model declarative-like memory functions and response-63 flexibility or working memory 9 .…”

mentioning

confidence: 99%

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Subtle behavioral changes and increased prefrontal-hippocampal network synchronicity in APPNL−G−F mice before prominent plaque deposition

Latif‐Hernandez

Shah

Craessaerts

et al. 2019

Behavioural Brain Research

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Amyloid-β (Aβ) peptides occur in the brains of patients with Alzheimer's disease (AD), but their role in functional impairment is still debated. High levels of APP and APP fragments in mice that overexpress APP might confound their use in preclinical research. We examined the occurrence of behavioral, cognitive and neuroimaging changes in APP knock-in mice that display Aβ42 amyloidosis in the absence of APP overexpression. Female APP mice (carrying Swedish, Iberian and Arctic APP mutations) were compared to APP mice (APP Swedish) at 3, 7 and 10 months. Mice were subjected to a test battery that referred to clinical AD symptoms, comprising cage activity, open field, elevated plus maze, social preference and novelty test, and spatial learning, reversal learning and spatial reference memory performance. Our assessment confirmed that behavior at these early ages was largely unaffected in these mice in accordance with previous reports, with some subtle behavioral changes, mainly in social and anxiety-related test performance. Resting-state functional MRI (rsfMRI) assessed connectivity between hippocampal and prefrontal regions with an established role in flexibility, learning and memory. Increased prefrontal-hippocampal network synchronicity was found in 3-month-old APP mice. These functional changes occurred before prominent amyloid plaque deposition.

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Section: Discussionsupporting

confidence: 91%

Section: Spatial Reversal Learning Defect In App Nl-g-f Micesupporting

confidence: 49%

Section: Introductionmentioning

confidence: 81%

mentioning

confidence: 99%

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Subtle behavioral changes and increased prefrontal-hippocampal network synchronicity in APPNL−G−F mice before prominent plaque deposition

Latif‐Hernandez

Shah

Craessaerts

et al. 2019

Behavioural Brain Research

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“…Accordingly, any dysfunction found in App NL-F KI but not App NL-G-F KI mice of ~9 months age, as here, can reasonably be attributed as the sequelae of specifically insoluble Aβ 42 aggregation. We therefore argue that specifically insoluble Distance travelled in the open field is significantly greater in 6 month old App NL-G-F KI mice, whilst at 8 months (the current study) and 10 months of age, there were no significant differences (Latif-Hernandez et al, 2017;Whyte et al, 2018), suggesting hyperactivity is only detectable in younger mice.…”

Section: Discussioncontrasting

confidence: 51%

Insoluble Aβ overexpression in an App knock-in mouse model alters microstructure and gamma oscillations in the prefrontal cortex, and social and anxiety-related behaviours

Pervolaraki

Hall

Foresteire

et al. 2018

Preprint

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We studied two new App knock-in mice models of Alzheimer's disease (App NL-F and App NL-G-F ), which generate elevated levels of Aβ 40 and Aβ 42 without the confounds associated with APP overexpression. This enabled us to assess changes in anxietyrelated and social behaviours, and neural alterations potentially underlying such changes, driven specifically by Aβ accumulation. App NL-G-F knock-in mice exhibited subtle deficits in tasks assessing social olfaction, but not in social motivation tasks.In anxiety-assessing tasks, App NL-G-F knock-in mice exhibited: 1) increased thigmotaxis in the Open Field (OF), yet; 2) reduced closed-arm, and increased openarm, time in the Elevated Plus Maze (EPM). Their ostensibly-anxiogenic OF profile, yet ostensibly-anxiolytic EPM profile, could hint at altered cortical mechanisms affecting decision-making (e.g. 'disinhibition'), rather than simple core deficits in emotional motivation. Consistent with this possibility, alterations in microstructure, glutamatergic-dependent gamma oscillations, and glutamatergic gene expression were all observed in the prefrontal cortex, but not the amygdala, of App NL-G-F knockin mice. Thus, insoluble Aβ overexpression drives prefrontal cortical alterations, potentially underlying changes in social and anxiety-related behavioural tasks.

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Hippocampal Degeneration and Behavioral Impairment During Alzheimer-Like Pathogenesis Involves Glutamate Excitotoxicity

et al. 2021

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The hallmarks of Alzheimer's disease (AD) pathology include senile plaques accumulation and neurofibrillary tangles, which is thought to underlie synaptic failure. Recent evidence however supports that synaptic failure in AD may instead be instigated by enhanced N-methyl-D-aspartate (NMDA) activity, via a reciprocal relationship between soluble amyloid-β (Aβ) accumulation and increased glutamate agonist. While previous studies have shown Aβ-mediated alterations to the glutamatergic system during AD, the underlying etiology of excitotoxic glutamate-induced changes has not been explored. Here, we investigated the acute effects of stereotaxic dentate gyrus (DG) glutamate injection on behavior and molecular expression of specific proteins and neurochemicals modulating hippocampal functions. Dependence of glutamate-mediated effects on NMDA receptor (NMDAR) hyperactivation was tested using NMDARs antagonist memantine. DG of Wistar rats (12-weeks-old) were bilaterally microinjected with glutamate (500 mM) with or without daily intraperitoneal (i.p.) memantine injection (20 mg/kg) for 14 days, while controls received either intrahippocampal/i.p. PBS or i.p. memantine. Behavioral characterization in open field and Y-maze revealed that glutamate evoked anxiogenic responses and perturbed spatial memory were inhibited by memantine. In glutamate-treated rats, increased NO expression was accompanied by marked reduction in profiles of glutathione-s-transferase and glutathione peroxidase. Similarly, glutamatemediated increase in acetylcholinesterase expression corroborated downregulation of synaptophysin and PSD-95, coupled with initiation of reactive astrogliosis (GFAP). While neurofilament immunolocalization/immunoexpression was unperturbed, we found glutamate-mediated reduction in neurogenic markers Ki67 and PCNA immunoexpression, with a decrease in NR2B protein expression, whereas mGluR1 remains unchanged. In addition, increased expression of apoptotic regulatory proteins p53 and Bax was seen in glutamate infused rats, corroborating chromatolytic degeneration of granule neurons in the DG. Interestingly, memantine abrogated most of the degenerative changes associated with glutamate excitotoxicity in this study. Taken together, our findings causally link acute glutamate dyshomeostasis in the DG with development of AD-related behavioral impairment and molecular neurodegeneration.

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Reduction in open field activity in the absence of memory deficits in the AppNL−G−F knock-in mouse model of Alzheimer’s disease

Cited by 52 publications

References 21 publications

Subtle behavioral changes and increased prefrontal-hippocampal network synchronicity in APPNL−G−F mice before prominent plaque deposition

Subtle behavioral changes and increased prefrontal-hippocampal network synchronicity in APPNL−G−F mice before prominent plaque deposition

Insoluble Aβ overexpression in an App knock-in mouse model alters microstructure and gamma oscillations in the prefrontal cortex, and social and anxiety-related behaviours

Hippocampal Degeneration and Behavioral Impairment During Alzheimer-Like Pathogenesis Involves Glutamate Excitotoxicity

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