Neurobiology of Alzheimer's Disease
Alzheimer's disease is a neurodegenerative disease and is the main cause of dementia in the elderly: it affects 3.5 million people in Europe, 400,000 of them in Spain. With increasing life expectancy, the incidence of the disease is expected to double in the coming years, but there is currently no cure or effective treatment. In histopathological terms, Alzheimer's is characterized by the accumulation of deposits of the protein ß-amyloid and of neurofibrillary tangles, which cause the death of the neurons in the hippocampus and the cortex, regions of the brain involved in learning and memory. Neuron death is preceded by synapse loss and alterations in neuron plasticity, which determine the onset of cognitive symptoms.
Our laboratory studies the cellular and molecular bases of cognitive deterioration in Alzheimer's with the aim of identifying new therapeutic targets and developing pharmacological treatments and gene-therapy treatments to delay or halt the progression of the disease. With this objective in mind, we use transgenic mice that overexpress the precursor protein of human amyloid (Tg2576 and APP/PS1) as experimental models. We have tools to evaluate the onset and progression of the disease in these models based on the analysis of molecular markers, histological markers (measurement of synaptic conductivity, amyloid pathology and tau), and batteries of behavioral tests that enable us to measure the degree of learning and the emotional and cognitive state of the animals.
Our laboratory was one of the first to identify alterations in the homeostasis of epigenetic processes, such as histone acetylation, and Alzheimer's models. This discovery provided the experimental basis for using histone-acetylation inhibitors (HDAC) as a therapy. We have also discovered other therapeutic targets, such as phosphodiesterases (PDE), and have shown that continued treatment with selective PDE5 inhibitors can revert symptoms in the Tg2576 model. In collaboration with the Molecular Therapy Platform, we have synthesized and are performing preclinical tests on new analogues with greater potency and fewer side effects. We have also used gene therapy to locally administer growth factors such as IGF2 to transgenic animals, thereby achieving significant improvements in behavior and amyloid pathology. Other lines of work have identified risk factors in Alzheimer's, such as stress, cholesterol and diabetes.