Characterization of cognitive deficits in a transgenic mouse model of Alzheimer's disease and effects of donepezil and memantine

Nagakura, Akira; Shitaka, Yoshitsugu; Yarimizu, Junko; Matsuoka, Naoki

doi:10.1016/j.ejphar.2012.12.023

Cited by 53 publications

(32 citation statements)

References 42 publications

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“…Clinically, the combination of memantine and donepezil has demonstrated efficacy for treating the symptoms of AD (Gareri et al, 2014). Consistent with our results, several preclinical studies also have indicated cognition-enhancing effects of memantine and donepezil with repeated administration in other mouse models of AD (Nagakura et al, 2013). Because memantine and donepezil have different and complementary mechanisms of action, together they potentially offer additional benefits in relation to the etiology of AD.…”

Section: Discussionsupporting

confidence: 86%

Protective effects of NMDA receptor antagonist, memantine, against senescence of PC12 cells: A possible role of nNOS and combined effects with donepezil

Ota

Ogawa

Ouchi

et al. 2015

Experimental Gerontology

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Section: Discussionsupporting

confidence: 86%

Protective effects of NMDA receptor antagonist, memantine, against senescence of PC12 cells: A possible role of nNOS and combined effects with donepezil

Ota

Ogawa

Ouchi

et al. 2015

Experimental Gerontology

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“…Damage to, and the loss of, cholinergic neurons in mouse models of AD is consistent with previous observations [56]. Our study has started to identify MDMx loss in neurons in an age-dependent amyloid toxicity model, and our results suggest that Aβ may be inducing MDMx degradation in neurons of the frontal cortex, including cholinergic neuronal populations [51].…”

Section: Discussionsupporting

confidence: 91%

Caspase-dependent degradation of MDMx/MDM4 cell cycle regulatory protein in amyloid β-induced neuronal damage

Colacurcio

Zyskind

Jordan‐Sciutto

et al. 2015

Neuroscience Letters

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MDMx/MDM4 is a negative regulator of the p53 tumor suppressor protein and is necessary for survival in dividing cells. MDMx is also expressed in postmitotic neurons, with prosurvival roles that are independent of its extensively described roles in carcinogenesis. We and others have shown a role for MDMx loss in neuronal death in vitro and in vivo in several neurodegenerative diseases. Further, we have recently shown that MDMx is targeted for proteolytic degradation by calcium-dependent proteases, calpains, in neurons in vitro, and that MDMx overexpression provided partial neuroprotection in a model of HIV-associated neurodegeneration. Here, we assessed whether amyloid β (Aβ)-induced MDMx degradation occurred in Alzheimer’s Disease (AD) models. Our data shows an age-dependent reduction in MDMx levels in cholinergic neurons within the cortex of adult mice expressing the swedish mutant of the amyloid precursor protein, APP in the Tg2576 murine model of AD. In vitro, Aβ treatment of primary cortical neurons led to the caspase-dependent MDMx degradation. Our findings suggest that MDMx degradation associated with neuronal death occurs via caspase activation in neurons, and that the progressive loss of MDMx protein represents a potential mechanism of Aβ-induced neuronal death during disease progression in AD.

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“…For example, compared with other APP and PS1 AD mouse models, such as the APP/PS1 model and the APP + PS1 model, the onset of cognitive deficits in the APP/PS1 KI model appears to occur slightly later in life. Both the APP + PS1 model and the APP/PS1 model show deficits at 4 to 6 months of age [36-39], whereas the APP/PS1 KI mice show deficits starting at 11 months old (Figure 3). …”

Section: Discussionmentioning

confidence: 99%

Comprehensive behavioral characterization of an APP/PS-1 double knock-in mouse model of Alzheimer's disease

Webster

Bachstetter

Eldik

2013

Alzheimers Res Ther

113

101

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IntroductionDespite the extensive mechanistic and pathological characterization of the amyloid precursor protein (APP)/presenilin-1 (PS-1) knock-in mouse model of Alzheimer's disease (AD), very little is known about the AD-relevant behavioral deficits in this model. Characterization of the baseline behavioral performance in a variety of functional tasks and identification of the temporal onset of behavioral impairments are important to provide a foundation for future preclinical testing of AD therapeutics. Here we perform a comprehensive behavioral characterization of this model, discuss how the observed behavior correlates with the mechanistic and pathological observations of others, and compare this model with other commonly used AD mouse models.MethodsFour different groups of mice ranging across the lifespan of this model (test groups: 7, 11, 15, and 24 months old) were run in a behavioral test battery consisting of tasks to assess motor function (grip strength, rotor rod, beam walk, open field ambulatory movement), anxiety-related behavior (open field time spent in peripheral zone vs. center zone, elevated plus maze), and cognitive function (novel object recognition, radial arm water maze).ResultsThere were no differences in motor function or anxiety-related behavior between APP/PS-1 knock-in mice and wild-type counterpart mice for any age group. Cognitive deficits in both recognition memory (novel object recognition) and spatial reference memory (radial arm water maze) became apparent for the knock-in animals as the disease progressed.ConclusionThis is the first reported comprehensive behavioral analysis of the APP/PS1 knock-in mouse model of AD. The lack of motor/coordination deficits or abnormal anxiety levels, coupled with the age/disease-related cognitive decline and high physiological relevance of this model, make it well suited for utilization in preclinical testing of AD-relevant therapeutics.

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Characterization of cognitive deficits in a transgenic mouse model of Alzheimer's disease and effects of donepezil and memantine

Cited by 53 publications

References 42 publications

Protective effects of NMDA receptor antagonist, memantine, against senescence of PC12 cells: A possible role of nNOS and combined effects with donepezil

Protective effects of NMDA receptor antagonist, memantine, against senescence of PC12 cells: A possible role of nNOS and combined effects with donepezil

Caspase-dependent degradation of MDMx/MDM4 cell cycle regulatory protein in amyloid β-induced neuronal damage

Comprehensive behavioral characterization of an APP/PS-1 double knock-in mouse model of Alzheimer's disease

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