A Novel hAPP/htau Mouse Model of Alzheimer's Disease: Inclusion of APP With Tau Exacerbates Behavioral Deficits and Zinc Administration Heightens Tangle Pathology

Lippi, Stephen L.P.; Smith, Meghann L.; Flinn, Jane M.

doi:10.3389/fnagi.2018.00382

Cited by 30 publications

(46 citation statements)

References 112 publications

(154 reference statements)

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“…For example, as demonstrated in Figure 4, 5.5-month-old P301L rTg4510 (htau) mice built significantly worse nests out of shredded paper compared to their age-matched wildtype counterparts 31 . Likewise, dual J20 (hAPP)/htau and single htau mice built poorer nests out of shredded paper compared to their wildtype and CAMKIIa-promoter only counterparts, both at 3.5-and 7-months of age 32 (data not shown).…”

Section: Representative Resultsmentioning

confidence: 91%

Nest Building Behavior as an Early Indicator of Behavioral Deficits in Mice

Neely

Pedemonte

Boggs

et al. 2019

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Nest building is an innate behavior in male and female rodents, even when raised in laboratory settings. As such, many researchers provide rodents synthetic and/or natural materials (such as twine, tissue, cotton, paper, and hay) as a gauge of their overall well-being and as an ancillary assessment to predict the possible decline in cognition. Typically, changes in nesting behaviors, such as failure to create a nest, indicate a change in health or welfare. In addition, nesting behavior is sensitive to many environmental and physiological challenges, as well as many genetic mutations underlying pathological disease states. The following protocol describes a nesting behavior paradigm that explores the usage of four types of nesting material. In addition, the protocol utilizes intraclass correlations to demonstrate that inter-rater reliability is higher when nests are constructed out of shredded paper compared to other common nesting materials such as cotton squares, paper twists, and soft cob bedding. The chosen methodology and statistical considerations (i.e., intraclass correlation) for this assay may be of interest for those conducting experiments assessing the quality of living of mice.

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Section: Representative Resultsmentioning

confidence: 91%

Nest Building Behavior as an Early Indicator of Behavioral Deficits in Mice

Neely

Pedemonte

Boggs

et al. 2019

JoVE

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“…Zinc does not affect daily activity rhythms in wildtype mice at 7 months, thus indicating that the reduced activity seen in the dual Tg mice is due to an interaction with Zn and amyloid or tau. The changes are not due to a loss of activity in general in the 7 month dual Tg mice since there were no significant differences in distance traveled in the open field test between dual and tau mice at this age (Lippi et al, 2018).…”

Section: The Role Of Zinc In Daily Rhythm Activitymentioning

confidence: 76%

“…We have shown that a novel mouse model, previously shown to exhibit deficits in both cognitive (Barnes maze) and noncognitive (burrowing and nesting) behaviors (Lippi et al, 2018), exhibited disturbances in wheel-running activity both early and FIGURE 1 | Comparison of dark cycle activity by (A) Genotype by age and (B) age by genotype. Wildtype animals showed significantly higher total dark cycle activity than dual Tg animals at 7 months; hourly differences showed dual Tg animals were significantly less active than wildtypes early in the dark cycle, ZT12-17 at 3.5 months and ZT12-16 at 7 months.…”

Section: Discussionmentioning

confidence: 99%

“…Mice in the current experiment underwent a battery of behavioral tests, including those to measure learning and memory (Barnes (Lippi et al, 2018). After burrowing and nesting behavior were assessed, and prior to forced swim activity data collection, mice were tested for daily wheel-running activity.…”

Section: Wheel Running (Daily Activity Rhythm Measurement)mentioning

confidence: 99%

“…Excess zinc causes impairments in many behaviors, including CR, in mice modeling AD which contain either human amyloid or human tau (Graybeal et al, 2015;Boggs et al, 2017;Craven et al, 2018). We have now examined changes in daily activity rhythm in a mouse model of AD containing both human amyloid and human tau (Lippi et al, 2018) and examined the effect of zinc administration in these mice. Mice were examined at both 3.5 and 7 months; sex differences in activity were also examined.…”

Section: Introductionmentioning

confidence: 99%

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Wheel-Running Behavior Is Negatively Impacted by Zinc Administration in a Novel Dual Transgenic Mouse Model of AD

et al. 2020

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Alzheimer's disease (AD) is a neurocognitive disorder that impacts both the brain and behavior. Metal ions, including zinc (Zn), have been seen to play an important role in AD-related pathology. In this study, we show alterations in wheel-running behavior both early and late in disease progression in a novel dual Tg mouse model of AD. This mouse includes both amyloid and tau pathology through its cross with the J20 (hAPP) and P301L (Tau) parentage. Animals were given either lab water or water that had been supplemented with 10 ppm Zn. Wheel running was assessed through individually housing mice and measuring wheel-running activity in both the light and dark cycles. Dual Tg mice showed significantly less activity in the first part of the dark cycle than WT mice at both 3.5 and 7 months of age (p < 0.05). Dual Tg mice given Zn water showed less activity compared to dual Tg mice on lab water, tau mice on Zn water, or WT mice given either lab or Zn water (p < 0.05) at 7 months. Female mice in this study consistently showed higher activity compared to male mice in all groups whereas Zn led to reduced activity. Daily activity rhythm was altered in both the tau and dual Tg mice, and Zn impacted this alteration through effects on amyloid, tau, and through circadian pathways.

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Decreased nesting behavior, selective increases in locomotor activity in a novel environment, and paradoxically increased open arm exploration in Neurogranin knockout mice

Nakajima

Funasaka

Huang

et al. 2020

Neuropsychopharm Rep

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Aims Neurogranin (NRGN) is a postsynaptic protein kinase substrate that binds calmodulin in the absence of calcium. Recent studies suggest that NRGN is involved in neuropsychiatric disorders, including schizophrenia, ADHD, and Alzheimer's disease. Previous behavioral studies of Nrgn knockout (Nrgn KO) mice identified hyperactivity, deficits in spatial learning, impaired sociability, and decreased prepulse inhibition, which suggest that these mice recapitulate some symptoms of neuropsychiatric disorders. To further validate Nrgn KO mice as a model of neuropsychiatric disorders, we assessed multiple domains of behavioral phenotypes in Nrgn KO mice using a comprehensive behavioral test battery including tests of homecage locomotor activity and nesting behavior. Methods Adult Nrgn KO mice (28‐54 weeks old) were subjected to a battery of comprehensive behavioral tests, which examined general health, nesting behavior, neurological characteristics, motor function, pain sensitivity, locomotor activity, anxiety‐like behavior, social behavior, sensorimotor gating, depression‐like behavior, and working memory. Results The Nrgn KO mice displayed a pronounced decrease in nesting behavior, impaired motor function, and elevated pain sensitivity. While the Nrgn KO mice showed increased locomotor activity in the open field test, these mice did not show hyperactivity in a familiar environment as measured in the homecage locomotor activity test. The Nrgn KO mice exhibited a decreased number of transitions in the light‐dark transition test and decreased stay time in the center of the open field test, which is consistent with previous reports of increased anxiety‐like behavior. Interestingly, however, these mice stayed on open arms significantly longer than wild‐type mice in the elevated plus maze. Consistent with previous studies, the mutant mice exhibited decreased prepulse inhibition, impaired working memory, and decreased sociability. Conclusions In the current study, we identified behavioral phenotypes of Nrgn KO mice that mimic some of the typical symptoms of neuropsychiatric diseases, including impaired executive function, motor dysfunction, and altered anxiety. Most behavioral phenotypes that had been previously identified, such as hyperlocomotor activity, impaired sociability, tendency for working memory deficiency, and altered sensorimotor gating, were reproduced in the present study. Collectively, the behavioral phenotypes of Nrgn KO mice detected in the present study indicate that Nrgn KO mice are a valuable animal model that recapitulates a variety of symptoms of neuropsychiatric disorders, such as schizophrenia, ADHD, and Alzheimer's disease.

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A Novel hAPP/htau Mouse Model of Alzheimer's Disease: Inclusion of APP With Tau Exacerbates Behavioral Deficits and Zinc Administration Heightens Tangle Pathology

Cited by 30 publications

References 112 publications

Nest Building Behavior as an Early Indicator of Behavioral Deficits in Mice

Nest Building Behavior as an Early Indicator of Behavioral Deficits in Mice

Wheel-Running Behavior Is Negatively Impacted by Zinc Administration in a Novel Dual Transgenic Mouse Model of AD

Decreased nesting behavior, selective increases in locomotor activity in a novel environment, and paradoxically increased open arm exploration in Neurogranin knockout mice

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