Effects of sub-chronic donepezil on brain Abeta and cognition in a mouse model of Alzheimer’s disease

Easton, Amy; Sankaranarayanan, Sethu; Tanghe, An; Terwel, Dick; Lin, Alan; Hoque, Nina; Bourin, Clotilde; Gu, Huidong; Ahlijanian, Michael K.; Bristow, Linda J.

doi:10.1007/s00213-013-3152-3

Cited by 27 publications

(20 citation statements)

References 67 publications

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“…The F1-hybrid strain was a crossing of heterozygous hAPP V717I males in C57Bl/6J background with wild-type FVB/N females, and double transgenic mice overexpressing hAPP Lon and hPS1 A246E were generated by cross-breeding the single hAPP Lon mutant with homozygous hPS1 A246E mice [ 30 ]. The age-dependent behavioural and histopathological phenotype of double transgenic hAPP Lon /hPS1 A246E mice has been reported previously [ 30 , 37 , 41 ]. All hAPP Lon /hPS1 A246E mice were genotyped by two independent PCR assays with primers specific for the mutant hAPP and hPS1 sequence on DNA extracts from tail biopsies sampled at the age of three weeks and three weeks before treatment start, respectively.…”

Section: Methodsmentioning

confidence: 57%

Long-Term Treatment with Liraglutide, a Glucagon-Like Peptide-1 (GLP-1) Receptor Agonist, Has No Effect on β-Amyloid Plaque Load in Two Transgenic APP/PS1 Mouse Models of Alzheimer’s Disease

et al. 2016

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One of the major histopathological hallmarks of Alzheimer’s disease (AD) is cerebral deposits of extracellular β-amyloid peptides. Preclinical studies have pointed to glucagon-like peptide 1 (GLP-1) receptors as a potential novel target in the treatment of AD. GLP-1 receptor agonists, including exendin-4 and liraglutide, have been shown to promote plaque-lowering and mnemonic effects of in a number of experimental models of AD. Transgenic mouse models carrying genetic mutations of amyloid protein precursor (APP) and presenilin-1 (PS1) are commonly used to assess the pharmacodynamics of potential amyloidosis-lowering and pro-cognitive compounds. In this study, effects of long-term liraglutide treatment were therefore determined in two double APP/PS1 transgenic mouse models of Alzheimer’s disease carrying different clinical APP/PS1 mutations, i.e. the ‘London’ (hAPPLon/PS1A246E) and ‘Swedish’ mutation variant (hAPPSwe/PS1ΔE9) of APP, with co-expression of distinct PS1 variants. Liraglutide was administered in 5 month-old hAPPLon/PS1A246E mice for 3 months (100 or 500 ng/kg/day, s.c.), or 7 month-old hAPPSwe/PS1ΔE9 mice for 5 months (500 ng/kg/day, s.c.). In both models, regional plaque load was quantified throughout the brain using stereological methods. Vehicle-dosed hAPPSwe/PS1ΔE9 mice exhibited considerably higher cerebral plaque load than hAPPLon/PS1A246E control mice. Compared to vehicle-dosed transgenic controls, liraglutide treatment had no effect on the plaque levels in hAPPLon/PS1A246E and hAPPSwe/PS1ΔE9 mice. In conclusion, long-term liraglutide treatment exhibited no effect on cerebral plaque load in two transgenic mouse models of low- and high-grade amyloidosis, which suggests differential sensitivity to long-term liraglutide treatment in various transgenic mouse models mimicking distinct pathological hallmarks of AD.

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Section: Methodsmentioning

confidence: 57%

Long-Term Treatment with Liraglutide, a Glucagon-Like Peptide-1 (GLP-1) Receptor Agonist, Has No Effect on β-Amyloid Plaque Load in Two Transgenic APP/PS1 Mouse Models of Alzheimer’s Disease

et al. 2016

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“…Among the different approaches tried, the inhibition of AChE is the most successful one (30). To date, AChE inhibitors are widely used to improve the cognitive impairments such as learning and memory ones in patients with Alzheimer’s disease through enhance acetylcholine levels at synapses where the neurotransmitter has been evacuated in order to degeneration of neuronal cells (31). …”

Section: Discussionmentioning

confidence: 99%

“…Donepezil at the dose of 2 mg/kg once a day for five consecutive days for two weeks improve spatial learning and memory deficits following traumatic brain injury independent of its effects on neurogenesis (16). Moreover, after treatment with donepezil a considerable improvement of memory as well as a dose-dependent depletion of amyloid-β (Aβ) was observed in brain of hAPP/PS1 mice (31). In gerbils, administratation donepezil at the dose of 5 mg/kg for 21 consecutive days reduced hippocampal neuro-degeneration and cognitive impairments after global cerebral ischemia (32).…”

Section: Discussionmentioning

confidence: 99%

Zataria Multiflora Boiss Improves Learning And Memory Impairment Induced By Toxoplasma Gondii Infection

Mahmoudvand¹,

Esmaeelpour²,

Ziaali³

et al. 2017

European Proceedings of Social and Behavioural Sciences

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Recent epidemiological and experimental studies also showed that latent toxoplasmosis can lead to a number of neurological and behavioral disorders such as learning and memory impairments. Recent studies showed that the essential oil and methanolic extract of the Zataria multiflora revealed a significant anticholinesterase activity on in vitro ().Here, we evaluated the effect of Z. multiflora essential oil to ameliorate learning and memory impairments induced by T. gondii infection in BALB/c mice. The animal model of Toxoplasma infection was established by the intraperitoneal inoculation of 20-25 tissue cysts from Tehran strain of T. gondii. Morris water maze (MWM) task was used to assay spatial learning and short term spatial memory in all groups. The findings revealed that in this study demonstrated that latent toxoplasmosis impaired spatial leaning and short term spatial memory of the infected BALB/c mice, while ZME, due having AChE inhibitor activity, improved impairments induced by Toxoplasma infection. The obtained findings demonstrated ZME as an AChE inhibitor to improves learning and memory disorders in mice with latent toxoplasmosis probably via restoring ACh levels in brain. However, additional studies are needed to clarify these mechanisms and also other possible ones.

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“…By and large, DON has shown to reverse scopolamine-induced learning deficits in reference and working memory tests in rodents [ 57 , 20 , 58 ]. Interestingly, a study performed in transgenic AD mice revealed that sub-chronic administration of DON for 2 weeks concomitantly improved the cognitive deficits along with the dose-dependent decrease of brain soluble and insoluble Aβ40 and 42 [ 59 ]. Consistent with preclinical studies, DON has been shown to counteract the negative impact of SD on cognitive function in a group of healthy individuals whose cognitive performance was greatly impaired by SD [ 60 , 61 ].…”

Section: Discussionmentioning

confidence: 99%

Effects of acute administration of donepezil or memantine on sleep-deprivation-induced spatial memory deficit in young and aged non-human primate grey mouse lemurs (Microcebus murinus)

et al. 2017

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The development of novel therapeutics to prevent cognitive decline of Alzheimer's disease (AD) is facing paramount difficulties since the translational efficacy of rodent models did not resulted in better clinical results. Currently approved treatments, including the acetylcholinesterase inhibitor donepezil (DON) and the N-methyl-D-aspartate antagonist memantine (MEM) provide marginal therapeutic benefits to AD patients. There is an urgent need to develop a predictive animal model that is phylogenetically proximal to humans to achieve better translation. The non-human primate grey mouse lemur (Microcebus murinus) is increasingly used in aging research, but there is no published results related to the impact of known pharmacological treatments on age-related cognitive impairment observed in this primate. In the present study we investigated the effects of DON and MEM on sleep-deprivation (SD)—induced memory impairment in young and aged male mouse lemurs. In particular, spatial memory impairment was evaluated using a circular platform task after 8 h of total SD. Acute single doses of DON or MEM (0.1 and 1mg/kg) or vehicle were administered intraperitoneally 3 h before the cognitive task during the SD procedure. Results indicated that both doses of DON were able to prevent the SD-induced deficits in retrieval of spatial memory as compared to vehicle-treated animals, both in young and aged animals Likewise, MEM show a similar profile at 1 mg/kg but not at 0.1mg/kg. Taken together, these results indicate that two widely used drugs for mitigating cognitive deficits in AD were partially effective in sleep deprived mouse lemurs, which further support the translational potential of this animal model. Our findings demonstrate the utility of this primate model for further testing cognitive enhancing drugs in development for AD or other neuropsychiatric conditions.

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Effects of sub-chronic donepezil on brain Abeta and cognition in a mouse model of Alzheimer’s disease

Abstract: These results suggest that the observed cognitive improvement produced by donepezil in Alzheimer's disease may be due, at least in part, to reduction of brain Aβ.

Cited by 27 publications

References 67 publications

Long-Term Treatment with Liraglutide, a Glucagon-Like Peptide-1 (GLP-1) Receptor Agonist, Has No Effect on β-Amyloid Plaque Load in Two Transgenic APP/PS1 Mouse Models of Alzheimer’s Disease

Long-Term Treatment with Liraglutide, a Glucagon-Like Peptide-1 (GLP-1) Receptor Agonist, Has No Effect on β-Amyloid Plaque Load in Two Transgenic APP/PS1 Mouse Models of Alzheimer’s Disease

Zataria Multiflora Boiss Improves Learning And Memory Impairment Induced By Toxoplasma Gondii Infection

Effects of acute administration of donepezil or memantine on sleep-deprivation-induced spatial memory deficit in young and aged non-human primate grey mouse lemurs (Microcebus murinus)

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