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Caccamo A, Maldonado MA, Bokov AF, Majumder S, Oddo S. CBP gene transfer increases BDNF levels and ameliorates learning and memory deficits in a mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A. 2010 Dec 28;107(52):22687-92. PubMed.
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Universitat Autonoma Barcelona
This is an interesting study that provides evidence that Aβ-induced memory deficits in 3xTg-AD transgenic mice are mediated through deregulation of the transcription factor CREB. The authors show reduced levels of phosphorylated CREB, a required step for CREB activation, in 3xTg-AD mice after a spatial learning task. Indeed, a role of CREB dysfunction on Aβ-induced memory deficits has been previously reported in other AD mouse models (Gong et al., 2004; España et al., 2010). Changes in CREB transcriptional activity induced by Aβ accumulation have been associated with memory deficits in APP transgenic mice (España et al., 2010), whereas pharmacological activation of PKA/CREB using rolipram reverses neuronal plasticity changes (Vitolo et al., 2002) and associative and spatial memory impairments in AD mouse models (Gong et al., 2004; Comery et al., 2005; Cheng et al., 2010). An intriguing question not elucidated in the present study is how a decrease of CREB phosphorylation causes learning deficits in 3xTg-AD mice. It is well established that training in spatial memory tasks induces expression of specific CREB target genes (Guzowski et al., 2001), and CREB is essential for long-lasting synaptic plasticity and memory but not for learning and short-term memory in both vertebrates and invertebrates (Bourtchuladze et al., 1994). In my view, the novelty of the present study is the finding that expression of the CREB coactivator CBP recovers the learning and memory deficits in 3xTg-AD mice, which suggests that Aβ impairs memory through CREB/CBP-dependent transcription. In support of this, expression of CBP enhances CREB phosphorylation and expression of the neurotrophic factor BDNF, a downstream CREB target gene involved in synaptic plasticity.
Further experiments will be necessary to discern the specific CREB/CBP target genes mediating memory loss in 3xTg-AD mice, and whether the beneficial effects of CBP on memory in AD models are due to its CREB co-transcriptional activity or histone acetyltransferase (HAT) activity. This is an important point, since previous studies indicated that both of these CBP activities are involved in long-term memory (Alarcon et al., 2004; Korzus et al., 2004), and histone deacetylase inhibitors ameliorates synapse loss and memory deficits in AD mouse models (Green et al., 2008; Kilgore et al., 2010; Ricobaraza et al., 2010). In summary, these new findings further support the therapeutic potential of activating CREB signaling for memory enhancement in AD.
References:
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España J, Valero J, Miñano-Molina AJ, Masgrau R, Martín E, Guardia-Laguarta C, Lleó A, Giménez-Llort L, Rodríguez-Alvarez J, Saura CA. beta-Amyloid disrupts activity-dependent gene transcription required for memory through the CREB coactivator CRTC1. J Neurosci. 2010 Jul 14;30(28):9402-10. PubMed.
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Guzowski JF, Setlow B, Wagner EK, McGaugh JL. Experience-dependent gene expression in the rat hippocampus after spatial learning: a comparison of the immediate-early genes Arc, c-fos, and zif268. J Neurosci. 2001 Jul 15;21(14):5089-98. PubMed.
Kilgore M, Miller CA, Fass DM, Hennig KM, Haggarty SJ, Sweatt JD, Rumbaugh G. Inhibitors of class 1 histone deacetylases reverse contextual memory deficits in a mouse model of Alzheimer's disease. Neuropsychopharmacology. 2010 Mar;35(4):870-80. PubMed.
Korzus E, Rosenfeld MG, Mayford M. CBP histone acetyltransferase activity is a critical component of memory consolidation. Neuron. 2004 Jun 24;42(6):961-72. PubMed.
Ricobaraza A, Cuadrado-Tejedor M, Marco S, Pérez-Otaño I, García-Osta A. Phenylbutyrate rescues dendritic spine loss associated with memory deficits in a mouse model of Alzheimer disease. Hippocampus. 2010 Nov 10; PubMed.
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Western Nevada College
There may be easier and safer ways to increase brain-derived growth factor. For example, eugenol (and probably a number of other phenols) increases levels of brain-derived neurotrophic factor in mice (Irie et al., 2004). Moreover, eugenol and other phenolic compounds (such as rosmarinic acid) protect against Aβ-induced memory deficits in mice (Alkam et al., 2007) and help prevent cell death caused by peroxynitrites (Chericoni et al., 2005, Irie 2006).
Eugenol can be found in a number of essential oils, including clove, true cinnamon, rosemary, and sage essential oils. One study suggested that eugenol may be a good medicine for Alzheimer's disease (Irie, 2006). A clinical trial using rosemary, lavender, lemon, and orange essential oils found "significant improvement in personal orientation related to cognitive function" in all patients with dementia who participated in the study, including patients with Alzheimer's disease. The conclusion from this clinical trial is that aromatherapy "is an efficacious non-pharmacological treatment for dementia. Aromatherapy may have some potential for improving cognitive function, especially in AD patients (Jimbo et al. 2010)." Although this was a very small trial of only 28 patients, lasting only 56 days, it could be that the answer to Alzheimer's disease is lying right under our noses if we care to look.
References:
Irie Y, Itokazu N, Anjiki N, Ishige A, Watanabe K, Keung WM. Eugenol exhibits antidepressant-like activity in mice and induces expression of metallothionein-III in the hippocampus. Brain Res. 2004 Jun 18;1011(2):243-6. PubMed.
Alkam T, Nitta A, Mizoguchi H, Itoh A, Nabeshima T. A natural scavenger of peroxynitrites, rosmarinic acid, protects against impairment of memory induced by Abeta(25-35). Behav Brain Res. 2007 Jun 18;180(2):139-45. PubMed.
Chericoni S, Prieto JM, Iacopini P, Cioni P, Morelli I. In vitro activity of the essential oil of Cinnamomum zeylanicum and eugenol in peroxynitrite-induced oxidative processes. J Agric Food Chem. 2005 Jun 15;53(12):4762-5. PubMed.
Irie Y. Effects of eugenol on the Central Nervous System: Its possible application to treatment of Alzheimer's disease, depression, and Parkinson's disease. Curr Bioact Comp 2006;2(1):57-66.
Jimbo D, Kimura Y, Taniguchi M, Inoue M, Urakami K. Effect of aromatherapy on patients with Alzheimer's disease. Psychogeriatrics. 2009 Dec;9(4):173-9. PubMed.
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