RESUMEN ANALÍTICO EN EDUCACIÓN RAE
1.1 MARCO DE REFERENCIA
1.1.7 El lenguaje audiovisual.
1.1.7.3 Movimientos de cámara
As noted in the introduction, soluble oligomers have been found by numerous studies to mediate neurotoxicity by inducing oxidative stress in the brain which promote TRPM2 activation, leading to a disruption in Ca2+ homeostasis and a toxic influx of Ca2+, ultimately inducing cell death (Goedert & Spillantini, 2006; Mattson, 2007;
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Takahashi et al., 2011). An improvement in memory in the TRPM2-KO- APPSWE/PSEN1∆E9 mice has been observed in our study and therefore knocking out TRPM2 has been found to be protective. Cognition was found to be mildly impaired in TRPM2-KO mice, as shown by impaired reversal learning. Future in vitro research could explore Aβ load in these TRPM2-KO individuals and see whether or not the load has decreased in these individuals since there was an improvement in behaviour. Presently, there are no specific antagonists of TRPM2. However, a number of pharmacological agents are able to inhibit the channel, although only non-selectively. These agents include flufenamic acid, econazole, clotrimazole, and N-(p-amycinnamoyl) (Eisfeld & Luckhoff, 2007; Olah et al., 2009). Thus, these potential TRPM2 antagonists should also be investigated in order to examine whether TRPM2 represents a target for the treatment of AD. Given our findings, we predict that a TRPM2 antagonist could potentially be effective in treating AD.
My study focuses on mice with TRPM2 absent from birth, which is different than humans who develop AD with age. To test the effectiveness of a TRPM2 blocker in patients already suffering the symptoms, longitudinal studies in which treatment is initiated at various time points (e.g. 3, 6, 9 months etc.) should be performed on mouse models of AD. In addition, biomarkers of AD may soon allow us to identify humans at risk of developing AD; treatment in these patients with a TRPM2 blocker could be considered.
88 4.9 Overall conclusions
Although the precise mechanism through which Aβ causes AD pathogenesis is not known at present, this mechanism can be speculated taking into consideration the large amount of research on this topic. To date, it is known that the accumulation of Aβ is the main pathological hallmarks of AD, and that Aβ induces oxidative stress and a loss of Ca2+ homeostasis in the brain. According to the amyloid cascade hypothesis, the accumulation of soluble Aβ peptides causes progressive synaptic and neuritic injury by reducing glutamatergic synaptic transmission strength and plasticity (Hardy, & Selkoe, 2002; Palop, & Mucke, 2010). Similarly, a loss of Ca2+ homeostasis is known to disrupt the structure and function of synapses, impair synaptic plasticity, and ultimately cause cell death. Although the precise mechanisms through which oxidative stress causes a loss of Ca2+ homeostasis is not known, we do know that oxidative stress promotes the activation of TRPM2 channels and that this activation causes a toxic influx of Ca2+ and ultimately induce cell death (Takahashi et al., 2011). Collectively, these findings led us to consider TRPM2 channels as a likely contributor to the neurotoxic cascades initiated by elevated Aβ levels.
This thesis was the first to explore the relationship between TRPM2 and cognitive deficits associated with a well characterized mouse model of Alzheimer’s disease. Our results suggest that knocking out the TRPM2 transgene improves the spatial learning and memory abilities of the APPSWE/PSEN1∆E9 double transgenic mice, suggesting that TRPM2 might represent a potential target for the treatment of AD.
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Section 5
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