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

doi:10.1016/j.bbr.2017.09.006

Behavioural Brain Research

Volume 336, 15 January 2018, Pages 177-181

https://doi.org/10.1016/j.bbr.2017.09.006 Get rights and content

Highlights

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App^NL−G−F mice show reduced open field activity at six months of age.
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Detection of memory deficits in six month App^NL−G−F mice may depend on environment.
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App^NL−G−F mouse brain shows widespread distribution of amyloid plaques at 29 weeks

Abstract

The recent development of knock-in mouse models of Alzheimer’s disease provides distinct advantages over traditional transgenic mouse models that rely on over-expression of amyloid precursor protein. Two such knock-in models that have recently been widely adopted by Alzheimer’s researchers are the App^NL−F and App^NL−G−F mice. This study aimed to further characterise the behavioural phenotype and amyloid plaque distribution of App^{NL−G−F/NL−G−F} (C57BL/6J background) mice at six-months of age. An attempt to replicate a previous study that observed deficits in working memory in the Y-maze, showed no difference between App^{NL−G−F/NL−G−F} and wild-type mice. Further assessment of these mice using the novel object recognition test and Morris water maze also revealed no differences between App^{NL−G−F/NL−G−F} and wild-type mice. Despite a lack of demonstrated cognitive deficits, we report a reduction in locomotor/exploratory activity in an open field. Histological examination of App^{NL−G−F/NL−G−F} mice showed widespread distribution of amyloid plaques at this age. We conclude that whilst at six-months of age, memory deficits are not sufficiently robust to be replicated in varying environments, amyloid plaque burden is significant in App^{NL−G−F/NL−G−F} knock-in brain.

Section snippets

Funding

LSW was awarded an Australian Rotary Health/Rotary Club of Adelaide Funding Partner Scholarship and an Australian Government Research Training Program Scholarship. Funding was also provided by the Lysosomal Diseases Research Unit, Nutrition and Metabolism Theme, SAHMRI. Funding bodies did not influence design or analysis of this study.

Acknowledgments

We thank Dr Stuart Howell for statistical advice, Leanne Hein for assistance with genotyping, Amanda Wilson for caring for the mice and Yi Ng for Slide Scanner operation.

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We have identified age-dependent cognitive learning and memory deficits using male C57BL/6 J (wild type, WT) and the knock-in APP^NL-F/NL-F (KI) aged 12, 15, and 18 months. An increase in the Aβ42/Aβ40 ratio and mouse ApoE levels in the hippocampus and frontal cortex preceded the onset of cognitive deficits in the KI mice. Moreover, dysfunction in insulin signaling, including increased IRS-1 serine phosphorylation in both brain areas and the tyrosine phosphorylation deficit in the frontal cortex, suggested age-dependent insulin/IGF-1 resistance. Resistance was reflected by disturbances in mTOR or ERK1/2 kinase phosphorylation and excessive pro-inflammatory (TNF-α, IL-6, and IL-23) status in the KI mice. Importantly, our study has provided insights into the higher vulnerability to PS-induced exacerbation of age-dependent cognitive deficits and biochemical dysfunction in KI mice than in WT animals.
We anticipate our study will lead to future investigation of a multi-faceted cause-and-effect relationship between stress during neurodevelopment and the onset of AD pathology, distinguishing it from changes in the course of dementia during normal ageing.
Modifying Dietary Protein Impacts mTOR Signaling and Brain Deposition of Amyloid β in a Knock-In Mouse Model of Alzheimer Disease
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Alzheimer disease (AD) is a neurodegenerative condition defined by the build-up of amyloid plaques in the brain and intraneuronal tangles of the protein tau. Autophagy is a cellular cleaning process involved in the degradation of proteins, including proteins directly responsible for amyloid plaques, but its activity is compromised in AD. The mechanistic target of rapamycin complex (mTORC) 1 inhibits autophagy when activated by amino acids.
We hypothesized that reducing amino acid intake by decreasing dietary protein could promote autophagy, which in turn could prevent amyloid plaque deposition in AD mice.
Homozygote (2-mo-old) and heterozygote (4-mo-old) amyloid precursor protein NL-G-F mice, a model of brain amyloid deposition, were used in this study to test this hypothesis. Male and female mice were fed with isocaloric low-protein, control, or high-protein diets for 4 mo and killed for analysis. Locomotor performance was measured using the inverted screen test, and body composition was measured using EchoMRI. Samples were analyzed using western blotting, enzyme-linked immunosorbent assay, mass spectrometry, and immunohistochemical staining.
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This study showed that reducing protein intake reduces mTORC1 activity and may prevent amyloid accumulation, at least in male mice. Moreover, dietary protein is a tool that can be used to change mTORC1 activity and amyloid deposition in the mouse brain, and the murine brain’s response to dietary protein is sex specific.
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Patients with early-onset Alzheimer's disease (EOAD) are at elevated risk for seizures, including patients with presenilin 2 (PSEN2) variants. Like people with epilepsy, uncontrolled seizures may worsen cognitive function in AD. While the relationship between seizures and amyloid beta accumulation has been more thoroughly investigated, the role of other drivers of seizure susceptibility in EOAD remain relatively understudied. We therefore sought to define the impact of loss of normal PSEN2 function and chronic seizures on cognitive function in the aged brain. Male and female PSEN2 KO and age- and sex-matched wild-type (WT) mice were sham or corneal kindled beginning at 6-months-old. Kindled and sham-kindled mice were then challenged up to 6 weeks later in a battery of cognitive tests: non-habituated open field (OF), T-maze spontaneous alternation (TM), and Barnes maze (BM), followed by immunohistochemistry for markers of neuroinflammation and neuroplasticity. PSEN2 KO mice required significantly more stimulations to kindle (males: p < 0.02; females: p < 0.02) versus WT. Across a range of behavioral tests, the cognitive performance of kindled female PSEN2 KO mice was most significantly impaired versus age-matched WT females. Male BM performance was generally worsened by seizures (p = 0.038), but loss of PSEN2 function did not itself worsen cognitive performance. Conversely, kindled PSEN2 KO females made the most BM errors (p = 0.007). Chronic seizures also significantly altered expression of hippocampal neuroinflammation and neuroplasticity markers in a sex-specific manner. Chronic seizures may thus significantly worsen hippocampus-dependent cognitive deficits in aged female, but not male, PSEN2 KO mice. Our work suggests that untreated focal seizures may worsen cognitive burden with loss of normal PSEN2 function in a sex-related manner.
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Lysosomal network abnormalities are an increasingly recognised feature of Alzheimer’s disease (AD), which appear early and are progressive in nature. Sandhoff disease and Tay-Sachs disease (neurological lysosomal storage diseases caused by mutations in genes that code for critical subunits of β-hexosaminidase) result in accumulation of amyloid-β (Aβ) and related proteolytic fragments in the brain. However, experiments that determine whether mutations in genes that code for β-hexosaminidase are risk factors for AD are currently lacking. To determine the relationship between β-hexosaminidase and AD, we investigated whether a heterozygous deletion of Hexb, the gene that encodes the beta subunit of β-hexosaminidase, modifies the behavioural phenotype and appearance of disease lesions in App^{NL-G-F/NL-G-F} (App^KI/KI) mice. App^KI/KI and Hexb^+/- mice were crossed and evaluated in a behavioural test battery. Neuropathological hallmarks of AD and ganglioside levels in the brain were also examined. Heterozygosity of Hexb in App^KI/KI mice reduced learning flexibility during the Reversal Phase of the Morris water maze. Contrary to expectation, heterozygosity of Hexb caused a small but significant decrease in amyloid beta deposition and an increase in the microglial marker IBA1 that was region- and age-specific. Hexb heterozygosity caused detectable changes in the brain and in the behaviour of an AD model mouse, consistent with previous reports that described a biochemical relationship between HEXB and AD. This study reveals that the lysosomal enzyme gene Hexb is not haplosufficient in the mouse AD brain.
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Transgenic mouse models of Aβ amyloidosis generated by knock-in of a humanized Aβ sequence can offer some advantages over the transgenic models that overexpress amyloid precursor protein (APP). However, systematic comparison of memory, behavioral, and neuropathological phenotypes between these models has not been well documented. In this study, we compared memory and affective behavior in APP^NLGF mice, an APP knock-in model, to two widely used mouse models of Alzheimer’s disease, 5xFAD and APP/PS1 mice, at 10 months of age. We found that, despite similar deficits in working memory, object recognition, and social recognition memory, APP^NLGF and 5xFAD mice but not APP/PS1 mice show compelling anxiety- and depressive-like behavior, and exhibited a marked impairment of social interaction. We quantified corticolimbic Aβ plaques, which were lowest in APP^NLGF, intermediate in APP/PS1, and highest in 5xFAD mice. Interestingly, analysis of plaque size revealed that plaques were largest in APP/PS1 mice, intermediate in 5xFAD mice, and smallest in APP^NLGF mice. Finally, we observed a significantly higher percentage of the area occupied by plaques in both 5xFAD and APP/PS1 relative to APP^NLGF mice. Overall, our findings suggest that the severity of Aβ neuropathology is not directly correlated with memory and affective behavior impairments between these three transgenic mouse models. Additionally, APP^NLGF may represent a valid mouse model for studying AD comorbid with anxiety and depression.

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

Highlights

Abstract

Section snippets

Funding

Acknowledgments

J. Biol. Chem.

J Biol Chem

Neurobiol Dis

Brain Res

Physiol Behav

Neurobiol Learn Mem

World Alzheimer Report, The Global Impact of Dementia, An Analysis of Prevalence, Incidence

Cost and Trends

Intraneuronal beta-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer's disease mutations: potential factors in amyloid plaque formation

J Neurosci

Targeted introduction of V642I mutation in amyloid precursor protein gene causes functional abnormality resembling early stage of Alzheimer’s disease in aged mice

Eur J Neurosci

Single App knock-in mouse models of Alzheimer’s disease

Nat Neurosci

Object recognition test in mice

Nat Protoc

Short communication
Reduction in open field activity in the absence of memory deficits in the App^NL−G−F knock-in mouse model of Alzheimer’s disease