Motor deficits in 16-month-old male and female 3xTg-AD mice

Montbrun, Thalia Garvock-de; Fertan, Emre; Stover, Kurt R.; Brown, Richard E.

doi:10.1016/j.bbr.2018.09.006

Cited by 32 publications

(35 citation statements)

References 84 publications

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“…APP+PS1 mice develop memory deficits at younger ages, similar to 5XFAD mice. Noteworthy, female and male 3xTg mice show memory impairments before the onset of motor deficits with 16 months of age (Garvock-de Montbrun et al, 2019), similar to Tg4-42 mice (Table 1), but memory deficits do not progress through age in 3xTg mice (Stevens and Brown, 2015). These inconsistent findings with regard to onset of memory and motor deficits should be considered when choosing a suitable mouse model for research, depending on the symptom of interest.…”

Section: Discussionmentioning

confidence: 79%

“…APP/PS1 KI mice did not show any motor deterioration and were comparable to controls at even older ages (Webster et al, 2013). Strikingly, male and female 3xTg mice performed better in rotarod task than controls up to the age of 16 months (Oore et al, 2013; Stover et al, 2015; Garvock-de Montbrun et al, 2019) (Table 1), but performance declined with age (Garvock-de Montbrun et al, 2019). Only Filali et al (2012) who tested only female 3xTg mice showed reduced performance in the rotarod, possibly due to protocol differences.…”

Section: Discussionmentioning

confidence: 99%

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Analysis of Motor Function in the Tg4-42 Mouse Model of Alzheimer’s Disease

Wagner

Sichler

Schleicher

et al. 2019

Front. Behav. Neurosci.

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Alzheimer’s disease (AD) is a neurodegenerative disorder and the most common form of dementia. Hallmarks of AD are memory impairments and cognitive deficits, but non-cognitive impairments, especially motor dysfunctions are also associated with the disease and may even precede classic clinical symptoms. With an aging society and increasing hospitalization of the elderly, motor deficits are of major interest to improve independent activities in daily living. Consistent with clinical findings, a variety of AD mouse models develop motor deficits as well. We investigated the motor function of 3- and 7-month-old Tg4-42 mice in comparison to wild-type controls and 5XFAD mice and discuss the results in context with several other AD mouse model. Our study shows impaired balance and motor coordination in aged Tg4-42 mice in the balance beam and rotarod test, while general locomotor activity and muscle strength is not impaired at 7 months. The cerebellum is a major player in the regulation and coordination of balance and locomotion through practice. Particularly, the rotarod test is able to detect cerebellar deficits. Furthermore, supposed cerebellar impairment was verified by 18 F-FDG PET/MRI. Aged Tg4-42 mice showed reduced cerebellar glucose metabolism in the 18 F-FDG PET. Suggesting that, deficits in coordination and balance are most likely due to cerebellar impairment. In conclusion, Tg4-42 mice develop motor deficits before memory deficits, without confounding memory test. Thus, making the Tg4-42 mouse model a good model to study the effects on cognitive decline of therapies targeting motor impairments.

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Section: Discussionmentioning

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Analysis of Motor Function in the Tg4-42 Mouse Model of Alzheimer’s Disease

Wagner

Sichler

Schleicher

et al. 2019

Front. Behav. Neurosci.

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“…By contrast, 3xTg-AD mice at both 6-months (Stover et al, 2015a) and 16-months (Garvock-de Montbrun et al, 2019) of age show improved performance as compared to WT controls on the rotarod test suggesting improved motor coordination. Importantly, however, 16-month old 3xTg-AD mice show an age-dependent deficit in performance on rotarod, grip strength, gait analysis and balance beam tests as compared to younger 6-month old 3xTg-AD mice (Garvock-de Montbrun et al, 2019). Overall, these findings underscore the importance of evaluating performance of 3xTg-AD mice on AD-related cognitive tasks in the context of potential motor abnormalities.…”

Section: Normal Motor Functionmentioning

confidence: 78%

Alcohol Drinking Exacerbates Neural and Behavioral Pathology in the 3xTg-AD Mouse Model of Alzheimer’s Disease

Hoffman

Faccidomo

Kim

et al. 2019

Preprint

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Alzheimer's disease (AD) is a progressive neurodegenerative disorder that represents the most common cause of dementia in the United States. Although the link between alcohol use and AD has been studied, preclinical research has potential to elucidate neurobiological mechanisms that underlie this interaction. This study was designed to test the hypothesis that non-dependent alcohol drinking exacerbates the onset and magnitude of AD-like neural and behavioral pathology.We first evaluated the impact of voluntary 24-h, 2-bottle choice home-cage alcohol drinking on the prefrontal cortex and amygdala neuroproteome in C57BL/6J mice and found a striking association between alcohol drinking and AD-like pathology. Bioinformatics identified the ADassociated proteins MAPT (Tau), amyloid beta precursor protein (APP), and presenilin-1 (PSEN-1) as the main modulators of alcohol-sensitive protein networks that included AD-related proteins that regulate energy metabolism (ATP5D, HK1, AK1, PGAM1, CKB), cytoskeletal development (BASP1, CAP1, DPYSL2 [CRMP2], ALDOA, TUBA1A, CFL2, ACTG1), cellular/oxidative stress (HSPA5, HSPA8, ENO1, ENO2), and DNA regulation (PURA, YWHAZ). To address the impact of alcohol drinking on AD, studies were conducted using 3xTg-AD mice that express human MAPT, APP, and PSEN-1 transgenes and develop AD-like brain and behavioral pathology. 3xTg-AD and wildtype mice consumed alcohol or saccharin for 4 months. Behavioral tests were administered during a 1-month alcohol free period. Alcohol intake induced AD-like behavioral pathologies in 3xTg-AD mice including impaired spatial memory in the Morris Water Maze, diminished sensorimotor gating as measured by prepulse inhibition, and exacerbated conditioned fear. Multiplex immunoassay conducted on brain lysates showed that alcohol drinking upregulated primary markers of AD pathology in 3xTg-AD mice: Aβ 42/40 ratio in the lateral entorhinal and prefrontal cortex and total Tau expression in the lateral entorhinal cortex and amygdala at 1-month post alcohol exposure. Immunocytochemistry showed that alcohol use upregulated expression of pTau (Ser199/Ser202) in the hippocampus, which is consistent with late stage AD. According to the NIA-AA Research Framework, these results suggest that alcohol use is associated with Alzheimer's pathology. Results also showed that alcohol use was associated with a general reduction in Akt/mTOR signaling via several phosphoproteins (IR, IRS1, IGF1R, PTEN, ERK, mTOR, p70S6K, RPS6) in multiple brain regions including hippocampus and entorhinal cortex.Dysregulation of Akt/mTOR phosphoproteins suggests alcohol may target this pathway in AD progression. These results suggest that nondependent alcohol drinking increases the onset and magnitude of AD-like neural and behavioral pathology in 3xTg-AD mice.

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“…Increased anxiety and depression-like behaviors have also been shown in the 3xTg-AD mice by 7 months of age (Romano et al, 2014; Zhang et al, 2016; Nie et al, 2017). However, these mice show better motor performance on the rotarod than wild-type (WT) controls (Stover et al, 2015a; Garvock-de Montbrun et al, 2019). In this study, male and female 3xTg-AD and WT mice were treated with DWG-1036 from 2 to 6 months of age and then tested in a behavioral test battery that measured spatial learning and memory, working memory, motor coordination and learning, anxiety, and depression.…”

Section: Introductionmentioning

confidence: 96%

Effects of the Novel IDO Inhibitor DWG-1036 on the Behavior of Male and Female 3xTg-AD Mice

et al. 2019

Self Cite

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The kynurenine pathway metabolizes tryptophan into nicotinamide adenine dinucleotide, producing a number of intermediary metabolites, including 3-hydroxy kynurenine and quinolinic acid, which are involved in the neurodegenerative mechanisms that underlie Alzheimer’s disease (AD). Indolamine 2,3-dioxygenase (IDO), the first and rate-limiting enzyme of this pathway, is increased in AD, and it has been hypothesized that blocking this enzyme may slow the progression of AD. In this study, we treated male and female 3xTg-AD and wild-type mice with the novel IDO inhibitor DWG-1036 (80 mg/kg) or vehicle (distilled water) from 2 to 6 months of age and then tested them in a battery of behavioral tests that measured spatial learning and memory (Barnes maze), working memory (trace fear conditioning), motor coordination and learning (rotarod), anxiety (elevated plus maze), and depression (tail suspension test). The 3xTg-AD mice treated with DWG-1036 showed better memory in the trace fear conditioning task and significant improvements in learning but poorer spatial memory in the Barnes maze. DWG-1036 treatment also ameliorated the behaviors associated with increased anxiety in the elevated plus maze and depression-like behaviors in the tail suspension test in 3xTg-AD mice. However, the effects of DWG-1036 treatment on the behavioral tasks were variable, and sex differences were apparent. In addition, high doses of DWG-1036 resulted in reduced body weight, particularly in females. Taken together, our results suggest that the kynurenine pathway is a promising target for treating AD, but more work is needed to determine the effective compounds, examine sex differences, and understand the side effects of the compounds.

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Motor deficits in 16-month-old male and female 3xTg-AD mice

Cited by 32 publications

References 84 publications

Analysis of Motor Function in the Tg4-42 Mouse Model of Alzheimer’s Disease

Analysis of Motor Function in the Tg4-42 Mouse Model of Alzheimer’s Disease

Alcohol Drinking Exacerbates Neural and Behavioral Pathology in the 3xTg-AD Mouse Model of Alzheimer’s Disease

Effects of the Novel IDO Inhibitor DWG-1036 on the Behavior of Male and Female 3xTg-AD Mice

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