Postsynaptic dysfunction is associated with spatial and object recognition memory loss in a natural model of Alzheimer’s disease

Centro Interdisciplinario de Neurociencia de Valparaíso, Facultad de Ciencias, Universidad de Valparaíso, 2360102 Valparaíso, Chile.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 08/2012; 109(34):13835-13840. DOI: 10.1073/pnas.1201209109


Alzheimer’s disease (AD) is an age-related neurodegenerative disorder associated with progressive memory loss, severe dementia,
and hallmark neuropathological markers, such as deposition of amyloid-β (Aβ) peptides in senile plaques and accumulation of
hyperphosphorylated tau proteins in neurofibrillary tangles. Recent evidence obtained from transgenic mouse models suggests
that soluble, nonfibrillar Aβ oligomers may induce synaptic failure early in AD. Despite their undoubted value, these transgenic
models rely on genetic manipulations that represent the inherited and familial, but not the most abundant, sporadic form of
AD. A nontransgenic animal model that still develops hallmarks of AD would be an important step toward understanding how sporadic
AD is initiated. Here we show that starting between 12 and 36 mo of age, the rodent Octodon degus naturally develops neuropathological signs of AD, such as accumulation of Aβ oligomers and phosphorylated tau proteins. Moreover,
age-related changes in Aβ oligomers and tau phosphorylation levels are correlated with decreases in spatial and object recognition
memory, postsynaptic function, and synaptic plasticity. These findings validate O. degus as a suitable natural model for studying how sporadic AD may be initiated.

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    • "There is evidence that aged subjects perform worse in different memory tasks in comparison with young subjects (Ming and song, 2005). Particularly, as regard to the object recognition in the O. degus, it has been demonstrated that aged animals are not able to recognize the novel object under normal sleep conditions (Ardiles et al., 2012). However , this disparity with our own results may be due to methodological differences. "
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    ABSTRACT: Memory loss is one of the key features of cognitive impairment in either aging, Mild Cognitive Impairment (MCI) or dementia. Pharmacological treatments for memory loss are today focused on addressing symptomatology. One of these approved compounds is memantine, a partial NMDA receptor antagonist that has proved its beneficial effects in cognition. The Octodon degus (O. degus) has been recently proposed as a potential model relevant for neurodegenerative diseases. However, there are no previous studies investigating the effect of pharmacological treatments for age-related cognitive impairment in this rodent. In this work we aimed to evaluate the effect of memantine on sleep deprivation (SD)-induced memory impairment in young and old O. degus. Young and old animals were trained in different behavioral paradigms validated for memory evaluation, and randomly assigned to a control (CTL, n=14) or an SD (n=14) condition, and treated with vehicle or memantine (10-mg/Kg i.p.) before the SD started. We demonstrate that SD impairs memory in both young and old animals, although the effect in the old group was significantly more severe (P < 0.05). Memantine pretreatment was able to prevent the cognitive impairment caused by SD in both age groups, while it had no negative effect on CTL animals. The positive effect of memantine in counteracting the negative effect of SD on the retrieval process even in the aged O. degus further supports the translational potential of both the challenge and the species, and will enable a better understanding of the behavioral features of memantine effects, especially related with reference and working memories.
    Neuropharmacology 05/2014; 85. DOI:10.1016/j.neuropharm.2014.05.023 · 5.11 Impact Factor
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    • "Perturbations in synapse formation and synaptic plasticity by pathological levels and forms of A␤ might be directly linked to the memory deficits in AD [29] [30]. In this study, we found that exposure of soluble A␤ 42 oligomers to cultured hippocampal neurons significantly decreased the density of dendritic filopodia. "
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    ABSTRACT: Rosiglitazone has been known to attenuate neurodegeneration in Alzheimer's disease (AD), but the underlying mechanisms remain to be fully elucidated. In this study, living-cell image, immunocytochemistry, and electrophysiology were used to examine the effects of soluble amyloid-β protein (Aβ) oligomers and rosiglitazone on the synapse formation, plasticity, and mitochondrial distribution in cultured neurons. Incubation of hippocampal cultures with amyloid-β (Aβ)42 oligomers (0.5 μM) for 3 h significantly decreased dendritic filopodium and synapse density. Pretreatment with rosiglitazone (0.5-5 μM) for 24 h prevented the Aβ42-induced loss of dendritic filopodium and synapse in a dose-dependent manner. However, neither Aβ42 oligomer nor rosiglitazone has a significant effect on the velocity and length of dendritic filopodia. Electrophysiological recording showed that acute exposure of slices with 0.5 μM Aβ42 oligomers impaired hippocampal long-term potentiation (LTP). Pre-incubation of hippocampal slices with rosiglitazone significantly prevented the Aβ42-induced LTP deficit, which depended on rosiglitazone concentrations (1-5 μM) and pretreatment period (1-5 h). The beneficial effects of rosiglitazone were abolished by the peroxisome proliferator-activated receptor gamma (PPARγ) specific antagonist, GW9662. Moreover, the mitochondrial numbers in the dendrite and spine were decreased by Aβ42 oligomers, which can be prevented by rosiglitazone. In conclusion, our data suggested that rosiglitazone prevents Aβ42 oligomers-induced impairment via increasing mitochondrial numbers in the dendrite and spine, improving synapse formation and plasticity. This process is most likely through the PPARγ-dependent pathway and in concentration and time dependent manners. The study provides novel insights into the mechanisms for the protective effects of rosiglitzone on AD.
    Journal of Alzheimer's disease: JAD 10/2013; 39(2). DOI:10.3233/JAD-130680 · 4.15 Impact Factor
    • "The situation may change as models become available for sporadic AD. A recent report of a “natural” model (age-related changes strongly reminiscent of AD in the rodent Octodon degus) may be grounds for optimism in this regard [60]. "
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    ABSTRACT: Progress in the development of therapeutic interventions to treat or slow the progression of Alzheimer's disease has been hampered by lack of efficacy and unforeseen side effects in human clinical trials. This setback highlights the need for new approaches for pre-clinical testing of possible interventions. Systems modelling is becoming increasingly recognised as a valuable tool for investigating molecular and cellular mechanisms involved in ageing and age-related diseases. However, there is still a lack of awareness of modelling approaches in many areas of biomedical research. We previously developed a stochastic computer model to examine some of the key pathways involved in the aggregation of amyloid-beta (Aβ) and the micro-tubular binding protein tau. Here we show how we extended this model to include the main processes involved in passive and active immunisation against Aβ and then demonstrate the effects of this intervention on soluble Aβ, plaques, phosphorylated tau and tangles. The model predicts that immunisation leads to clearance of plaques but only results in small reductions in levels of soluble Aβ, phosphorylated tau and tangles. The behaviour of this model is supported by neuropathological observations in Alzheimer patients immunised against Aβ. Since, soluble Aβ, phosphorylated tau and tangles more closely correlate with cognitive decline than plaques, our model suggests that immunotherapy against Aβ may not be effective unless it is performed very early in the disease process or combined with other therapies.
    PLoS ONE 09/2013; 8(9):e73631. DOI:10.1371/journal.pone.0073631 · 3.23 Impact Factor
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