DEVELOPMENT OF NON INVASIVE THERAPEUTICAL STRATEGIES TO AMELIORATE MEMORY DEFICITS, SYNAPTIC PLASTICITY AND NEURODEGENERATION IN A COMPREHENSIVE MOUSE MODEL FOR ALZHEIMER’S DISEASE

Alzheimer's Disease (AD) is a genetically complex neurodegenerative disorder which affects more than 12 million patients worldwide, being by far the most frequent cause of dementia. In patients with this devastating disorder memory becomes progressively more impaired and eventually also the capacities for reasoning decline. Effective therapeutical strategies in AD are lacking. Recently, a new mouse model for AD was derived, the AD11 mouse. This mouse develops an age dependent neurodegeneration which encompasses all hallmarks of human AD. Our first aim is to assess the time course of the memory and of synaptic plasticity deficits in AD11 mice and to correlate this time course with that of alterations in the cholinergic system, which is strongly affected in human AD. These results will contribute to develop new pharmaceutical tools. Our second aim is to explore the possibility to ameliorate memory deficits and neural plasticity, to arrest neurodegeneration and promote the replacement of lost cells in AD11 mice with non invasive therapeutical strategies. Three different strategies will be explored: treatment with Galantamine (Gal), an approved AD drug, non invasive nasal delivery of neurotrophins (NT) and exposure to a stimulating environment (environmental enrichment, EE). EE and NT enhance the ability to learn and remember. Experiments in animals have related this effect with the generation of new neurons in the hippocampus, a neural structure crucial for memory and have shown that EE and NT prevent the death of nervous cells. EE slows disease progression in a mouse model of another devastating neurodegenerative disorder, the Huntington's disease. We shall test whether these strategies can prevent, arrest, or even reverse neurodegeneration and memory deficits in AD11 mice. These results would have a direct bearing for human AD, since they will suggest whether EE and non invasive NT delivery could have effects on disease progression in humans.