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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    • "c o m / l o c a t e / y n l m e old O. degus acquires neuropathological signs of AD (Ardiles et al., 2012). O. degus spontaneously accumulates b-amyloid deposits from thirty-six months in the cortex and sixty in the hippocampus homologous to those detected in several cases of AD (Ardiles et al., 2012; Inestrosa et al., 2005) and can develop cognitive deficits (Van Groen et al., 2011), anxiety (Popovic et al., 2009) and inconstant circadian rhythms of low amplitude (Vivanco, Ortiz, Rol, & Madrid, 2007), as perceived in people with AD. O. degus has newly been recognized as a good research model in medicinal and therapeutic fields, principally those related with neurodegenerative disease where aging is involved (Tarragon et al., 2013). "
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    ABSTRACT: The benefits of neuromodulatory procedures as a possible therapeutic application for cognitive rehabilitation have increased with the progress made in non-invasive modes of brain stimulation in aged-related disorders. Transcranial magnetic stimulation (TMS) is a non-invasive method used to examine multiple facets of the human brain and to ameliorate the impairment in cognition caused by Alzheimer's disease (AD). The present study was designed to evaluate how a chronic TMS treatment could improve learning and memory functions after sleep deprivation (SD) in old O. degus. SD was executed by gently handling to keep the animals awake throughout the night. Thirty young and twenty-four old O. degus females were divided in six groups (control, acute and chronic TMS treatment). Behavioral tests included; Radial Arm Maze (RAM), Barnes Maze (BM) and Novel Object Recognition (NOR). Although learning and memory functions improved in young animals with only one session of TMS treatment, a significant improvement in cognitive performance was seen in old animals after 4 and 7 days of TMS, depending on the task that was performed. No side effects were observed following, which showed therapeutic potential for improving age-related cognitive performance.
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    • "degus) rodents. In order to establish the accuracy of TMS in O. degus and the suitability for posterior applications during aging-associated diseases such as neurodegenerative disorders (Ardiles et al. 2012; Babiloni et al. 2013, 2014), adult O. degus were evaluated under the SD paradigm. SD induces cognitive deficits in O. degus (Tarragon et al. 2014) and TMS treatment was assayed by three different behavioral studies: one working memory analysis (novel object recognition, NOR) and two hippocampal-dependent tests (RAM, and Barnes maze, BM) due to the hippocampus involvement in episodic, spatial, and semantic human memory (Spiers and Bendor 2014). "
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    ABSTRACT: Sleep is indispensable for maintaining regular daily life activities and is of fundamental physiological importance for cognitive performance. Sleep deprivation (SD) may affect learning capacity and the ability to form new memories, particularly with regard to hippocampus-dependent tasks. Transcranial magnetic stimulation (TMS) is a non-invasive procedure of electromagnetic induction that generates electric currents, activating nearby nerve cells in the stimulated cortical area. Several studies have looked into the potential therapeutic use of TMS. The present study was designed to evaluate how TMS could improve learning and memory functions following SD in Octodon degus. Thirty juvenile (18 months old) females were divided into three groups (control, acute, and chronic TMS treatment-with and without SD). TMS-treated groups were placed in plastic cylindrical cages designed to keep them immobile, while receiving head magnetic stimulation. SD was achieved by gently handling the animals to keep them awake during the night. Behavioral tests included radial arm maze (RAM), Barnes maze (BM), and novel object recognition. When TMS treatment was applied over several days, there was significant improvement of cognitive performance after SD, with no side effects. A single TMS session reduced the number of errors for the RAM test and improved latency and reduced errors for the BM test, which both evaluate spatial memory. Moreover, chronic TMS treatment brings about a significant improvement in both spatial and working memories.
    Full-text · Article · Jul 2015 · Neurotoxicity Research
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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.
    Full-text · Article · May 2014 · Neuropharmacology
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