Loss of memory reversed in Alzheimer's mice models
24.04.2014 Research  -  Researchers from the UAB Institute of Neuroscience have been able to reverse memory loss in its initial stages in model mice with Alzheimer's disease through gene therapy. The research appears on the cover of The Journal of Neuroscience.

Alzheimer's disease is the first cause of dementia and affects some 400,000 people in Spain alone. However, no effective cure has yet been found. One of the reasons for this is the lack of knowledge on the cellular mechanisms which cause alterations in nerve transmissions and the loss of memory in the initial stages of the disease.

Researchers from the Institute of Neuroscience at the Universitat Autònoma de Barcelona have discovered the cellular mechanism involved in memory consolidation and were able to develop a gene therapy which reverses the loss of memory in mice models with initial stages of Alzheimer's disease. The therapy consists in injecting into the hippocampus - a region of the brain essential to memory processing - a gene which causes the production of a protein blocked in patients with Alzheimer's, the “Crtc1” (CREB regulated transcription coactivator-1). The protein restored through gene therapy gives way to the signals needed to activate the genes involved in long-term memory consolidation.
To identify this protein, researchers compared gene expression in the hippocampus of healthy control mice with that of transgenic mice which had developed the disease. Through DNA microchips scientists identified the genes ("transcriptome") and the proteins ("proteome") which expressed themselves in each of the mice in different phases of the disease. Researchers observed that the set of genes involved in memory consolidation coincided with the genes regulating Crtc1, a protein which also controls genes related to the metabolism of glucose and to cancer. The alteration of this group of genes could cause memory loss in the initial stages of Alzheimer's disease.

In persons with the disease, the formation of amyloid plaque aggregates, a process known to cause the onset of Alzheimer's disease, prevents the Crtc1 protein from functioning correctly. “When the Crtc1 protein is altered, the genes responsible for the synapsis or connections between neurons in the hippocampus cannot be activated and the individual cannot perform memory tasks correctly”, explains Carlos Saura, researcher of the UAB Institute of Neuroscience and head of the research. According to Saura, “this study opens up new perspectives on therapeutic prevention and treatment of Alzheimer's disease, given that we have demonstrated that gene therapy which activates the Crtc1 protein is effective in preventing the loss of memory in lab mice".

The research, published today on the front page of The Journal of Neuroscience, the official journal of the US Society of Neuroscience, paves the way to a new therapeutic approach to the disease. One of the main challenges in finding a treatment for the disease in the future is to research and develop pharmacological therapies which can activate the Crtc1 protein, with the aim of preventing, slowing down or reverting the cognitive alterations in patients.

Image: Detection of the Crtc1 protein in hippocampus neurons in mice. The protein can be seen in red.

Original article: Parra-Damas A., Valero J., Chen M., España J., Martin E., Ferrer I., Rodríguez-Alvarez J. and Saura C.A. "CRTC1 activates a transcriptional program deregulated at early Alzheimer's disease-related stages" (2014). J. Neuroscience. 34(17)
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