Catalan researchers develop gene therapy reversing memory loss in mice with early-stage Alzheimer's

Barcelona (ACN).- Scientists at the Universitat Autònoma de Barcelona (UAB) have found that an alteration of a neuronal gene program plays an essential role in the first stages of Alzheimer´' disease in humans and have developed a gene therapy which is effective on mice, reversing their memory loss. The Catalan study occupies the front page of 'The Journal of Neuroscience'. Researchers have identified a new mechanism that regulates expression of genes in the brain that are essential for function of neuronal circuits involved in learning and memory. The mechanism has been found through mouse models and later verified in human brains at early pathological stages of Alzheimer's Disease. According to the new study, which has been carried out by Dr. Carlos Saura's group at the UAB's Institute of Neurosciences (Institut de Neurociències), the alteration of a gene program mediating neuronal transmission and survival may underlie memory loss at early pathological stages of Alzheimer's disease (AD). The gene therapy consists in inoculating a gene in the hippocampus that produces a protein – Crtc1 – which is blocked in Alzheimer's patients. The protein, which has been reactivated through gene therapy, produces a series of biochemical signals that activate the genes involved the consolidation of long-term memory.

Alzheimer´s disease is the main cause of dementia, affecting 400,000 people in Spain alone; however this disease has no effective treatment as yet.  One of the reasons is that the cellular mechanisms underlying changes in neuronal transmission and memory loss at early stages of the disease are unknown.

A protein in the hippocampus that activates genes involved in memory processing

In the new study, announced on the front page and published in 'The Journal of Neuroscience' – the official research journal of US Society for Neuroscience – the scientists analysed the progression of pathology and cognitive deficits during aging in an AD mouse model. Extensive transcriptome analysis of genes in the hippocampus, a brain region involved in encoding and storage of declarative memory that is affected in AD, revealed altered expression of a gene program essential for neuronal function coinciding with the first memory deficits. These findings were verified in human brains at early pathological stages of the disease.

Surprisingly, the researchers found that the molecule that regulates this set of genes is the transcriptional co-activator Crtc1, a protein that regulates genes involved in glucose metabolism and cancer.  "In the hippocampus, Crtc1 is activated during memory processing, but its inactivation causes alteration of a gene program essential for memory storage, disturbing the capability of a person to remember correctly" says Dr. Saura. 

A study opening the door to future therapies

According to Dr. Saura  this study opens "new perspectives in the prevention and therapeutic treatment of AD, since we have demonstrated that a gene therapy that activates Crtc1 is effective in preventing memory impairment in a mouse model of AD".  The study states that one of the future goals for the treatment of this devastating disease is the development of pharmacological therapies that activate Crtc1 to prevent, ameliorate or reverse cognitive impairments in AD patients. These future investigations will be possible as a result of funding by an American foundation aimed at combating AD and other neurological disorders.