Overview
Age plays a major role in most neurodegenerative disorders. For example, AD incidence rises exponentially with time, roughly doubling every five years. Age can determine neurodegenerative pathologies by a number of means, from the activation/inactivation of particular genes to environmental alteration of biochemical pathways. Moreover, the genetic or environmental causes can hit directly the nervous system or act at this level indirectly, by altering normal body homeostasis. In any event, age is a sine qua non condition for neurodegeneration and it is therefore our main aim to understand as much as possible about normal aging to then attempt to understand pathological aging. One potential mechanism to explain why certain genetic factors (such as the E4 allele of ApoE) or systemic alterations (such as obesity) predispose to AD might be the simple exacerbation of the otherwise normal deterioration with age. However, not all E4 carriers or obese people develop AD, indicating that individual control mechanisms are at play. These mechanisms may be protective, and therefore will prevent (or delay) the appearance of the disease in predisposed individuals. Alternative, these mechanisms may facilitate the development of the disease. Moreover, it is well known that AD has a precise anatomical correlate, in which the first signs appear in the enthorinal cortex, and then extend to the hippocampus, cingular cortex and other cortical regions, while sparing visual cortex. In order to determine the mechanisms by which normal aging proceeds or is diverted towards AD, we will employ a combination of experimental strategies. On the one hand, we will identify potential biochemical pathways involved in pathological aging by using bioinformatics and public databases of gene expression in different brain regions from affected and healthy people. In parallel, we will study brain function during normal aging at the cellular and organism levels. This way we will identify the precise function of the gene candidates derived from the bio-informatics approach. And finally, we will determine the diagnostic and therapeutic relevance of specific genetic and biochemical alterations using well established animal models of aging and AD, as well as human samples from patients. To accomplish these goals we have assembled a network with clinical investigators specialists in the diagnosis and treatment of AD affected individuals, as well as experts in mouse genetics and behavior, cell biology, neuronal and glia molecular biology and physiology, vascular biology and cancer research. While three groups have a past record in aging and AD (Dotti, Molinuevo, Sanfeliu) the remaining come from different disciplines, including cell death/survival balance in neurons (de la Rosa) and cancer cells (Nebreda), in the molecular basis of synaptic communication in neurons (Esteban) and neuron-glia (Araque) and in vascular biology (Moro). This multidisciplinary network ensures that brain aging will be then tackled using conventional and non-conventional strategies, with novel conceptual and technical approaches ranging from molecular to whole-animal and clinical studies. Naturally, to facilitate integration several steps have been taken, including the hosting of students from different groups in the laboratories of the partners. Given its high technology transfer potential, we have in the team the expertise in technology development and translation into the clinic. All in all, the ultimate goal of our study is to unravel the mechanisms that are responsible for brain dysfunction during normal aging and how they might go astray leading to neurodegenerative diseases such as AD and, from there, to develop tools for the early diagnosis of pathology as well as for its prevention and/or cure.