RESULTS: In comparison with 5-month-old mice, 18- to 19-month-old mice exhibited a severe and specific memory impairment in a contextual serial discrimination (CSD) task involving the learning and remembering of two successive spatial discriminations carried out on two distinct floors. This impairment was specific, as spatial memory, simultaneously tested on a simple discrimination (SD) task, was not affected in these aged mice. This deficit was completely reversed by 9-day per os administration of S 24795, a partial agonist of alpha 7 nicotinic receptors, at either 0.3 or 1.0 mg/kg. Memantine, an NMDA receptor antagonist, also had a memory-enhancing effect at a dose of 3.0 mg/kg, but not at 0.3 mg/kg. CONCLUSIONS: The memory-enhancing effect of S 24795 was due to a strong enhancement of contextual memory as indicated by a decrease in interference rate, whereas memantine enhanced spatial/semantic memory. S 24795 was more effective than memantine and also appears to be more specific to flexible forms of memory, one of the first cognitive domains (i.e. episodic memory) affected in Alzheimer's disease.
"However, although elevated levels of plasma CORT have been largely hypothesized to contribute to age-related memory decline (Cameron and Gould, 1994; Lupien et al., 1998; Yau and Seckl, 2012), few studies focus on the measurement of intrahippocampal CORT levels in aged rodents in relation to memory retrieval performance. Interestingly, it has been recently shown that stress-induced intrahippocampal CORT rise in middle-aged rats was associated with memory impairments in a hippocampal-dependent memory task (Chauveau et al., 2009b) that has been previously shown to be affected in middle-aged mice (Celerier et al., 2004; Beracochea et al., 2008a,b; Chauveau et al., 2009a,b; Pierard et al., 2009; Tronche et al., 2010). The magnitude of intracellular CORT action in the rodent hippocampus is thought to be determined by the hippocampal activity of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), an enzyme that regenerates active CORT within cells, but also by free CORT circulating in blood and delivered to the brain (Seckl, 1997). "
[Show abstract][Hide abstract] ABSTRACT: It is now established that vitamin A and its derivatives, retinoic acid (RA), are required for cognitive functions in adulthood. RA hyposignaling and hyperactivity of glucocorticoid (GC) pathway appear concomitantly during aging and would contribute to the deterioration of hippocampal synaptic plasticity and functions. Furthermore, recent data have evidenced counteracting effects of retinoids on GC signaling pathway. In the present study, we addressed the following issue: whether the stimulation of RA pathway could modulate intrahippocampal corticosterone (CORT) levels in middle-aged mice and thereby impact on hippocampal plasticity and cognitive functions. We firstly investigated the effects of vitamin A supplementation and RA treatment in middle-aged mice, on contextual serial discrimination task, a paradigm which allows the detection of early signs of age-related hippocampal-dependent memory dysfunction. We then measured intrahippocampal CORT concentrations by microdialysis before and after a novelty-induced stress. Our results show that both RA treatment and vitamin A supplementation improve "episodic-like" memory in middle-aged mice but RA treatment appears to be more efficient. Moreover, we show that the beneficial effect of RA on memory is associated to an increase in hippocampal PSD-95 expression. In addition, intrahippocampal CORT levels are reduced after novelty-induced stress in RA-treated animals. This effect cannot be related to a modulation of hippocampal 11β-HSD1 expression. Interestingly, RA treatment induces a modulation of RA receptors RARα and RARβ expression in middle-aged mice, a finding which has been correlated with the amplitude of intrahippocampal CORT levels after novelty-induced stress. Taken together, our results suggest that the preventive action of RA treatment on age-related memory deficits in middle-aged mice could be, at least in part, due to an inhibitory effect of retinoids on GC activity.
"Nonetheless, the neuroprotective role of nAChRs by counterbalancing the toxicity of Aβ oligomers has been proposed based on experimental observation . For example, drugs like 2-(2-(4-bromophenyl)-2-oxoethyl)-1-methyl pyridinium (S 24, 795), which have been assessed to be able to reduce the interaction between Aβ and nAChRs, have been shown to enhance long-term potentiation [110–112]. Interestingly, one research group has found that Aβ does not bind with nAChRs and has no direct relationship with the nAChRs expression and activity. Instead, the Aβ may affect the nAChRs indirectly by attaching to the membrane and altering the property of the membrane, which then influences the membrane receptors inadvertently . "
[Show abstract][Hide abstract] ABSTRACT: In this review, we elucidate the mechanisms of Aβ oligomer toxicity which may contribute to Alzheimer's disease (AD). In particular, we discuss on the interaction of Aβ oligomers with the membrane through the process of adsorption and insertion. Such interaction gives rises to phase transitions in the sub-structures of the Aβ peptide from α-helical to β-sheet structure. By means of a coarse-grained model, we exhibit the tendency of β-sheet structures to aggregate, thus providing further insights to the process of membrane induced aggregation. We show that the aggregated oligomer causes membrane invagination, which is a precursor to the formation of pore structures and ion channels. Other pathological progressions to AD due to Aβ oligomers are also covered, such as their interaction with the membrane receptors, and their direct versus indirect effects on oxidative stress and intraneuronal accumulation. We further illustrate that the molecule curcumin is a potential Aβ toxicity inhibitor as a β-sheet breaker by having a high propensity to interact with certain Aβ residues without binding to them. The comprehensive understanding gained from these current researches on the various toxicity mechanisms show promises in the provision of better therapeutics and treatment strategies in the near future.
International Journal of Molecular Sciences 12/2012; 13(6):7303-27. DOI:10.3390/ijms13067303 · 2.86 Impact Factor
"Aged rats that were unimpaired in a spatial memory task showed greater age-related declines in MK801 binding in the cortex and hippocampus than those that were impaired (Le Jeune et al., 1996). NMDA receptor antagonists, including mementine, a therapeutic used for AD, improve memory (Norris and Foster, 1999; Danysz and Parsons, 2003; Pieta Dias et al., 2007; Beracochea et al., 2008) and increase neurogenesis (Nacher et al., 2003) in aged individuals . Cholinesterase inhibitors used to treat AD are also believed to act by inhibiting NMDA receptors (Chen et al., 2008). "
[Show abstract][Hide abstract] ABSTRACT: N-methyl-D-aspartate (NMDA) receptors are present in high density within the cerebral cortex and hippocampus and play an important role in learning and memory. NMDA receptors are negatively affected by aging, but these effects are not uniform in many different ways. This review discusses the selective age-related vulnerabilities of different binding sites of the NMDA receptor complex, different subunits that comprise the complex, and the expression and functions of the receptor within different brain regions. Spatial reference, passive avoidance, and working memory, as well as place field stability and expansion all involve NMDA receptors. Aged animals show deficiencies in these functions, as compared to young, and some studies have identified an association between age-associated changes in the expression of NMDA receptors and poor memory performance. A number of diet and drug interventions have shown potential for reversing or slowing the effects of aging on the NMDA receptor. On the other hand, there is mounting evidence that the NMDA receptors that remain within aged individuals are not always associated with good cognitive functioning. This may be due to a compensatory response of neurons to the decline in NMDA receptor expression or a change in the subunit composition of the remaining receptors. These studies suggest that developing treatments that are aimed at preventing or reversing the effects of aging on the NMDA receptor may aid in ameliorating the memory declines that are associated with aging. However, we need to be mindful of the possibility that there may also be negative consequences in aged individuals.
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