Biological therapies for Alzheimer's disease: focus on trophic factors

Recent revolutionary discoveries in the structure and function of the nervous system have substantiated the early optimism expressed by Ramon y Cajal on the regenerative potential of neurons. A systematic study of the mechanisms of neural injury and repair has generated exciting new ideas on how to assist the innate restorative potential of the nervous system by using substances that address specific pathogenetic events (biological or rational therapies). The greatest challenge for these interventions is the prevention of neuronal cell death, which is the inevitable outcome of many common diseases of the nervous system and which limits the efficacy of more traditional treatment approaches (i.e., approaches to restore the neuronal phenotype). Trophic factors are excellent candidates because they are naturally implemented to promote the survival of neurons in development. Among many neurological diseases, Alzheimer's disease (AD) is a model for consideration of a trophic therapy because of its grave epidemiological impact and the massive death of neurons in multiple brain sites. In the present paper, we propose an approach to design trophic therapies for AD, considering also the pertinent clinical and ethical issues. We also integrate the trophic approach with other ways to promote neural regeneration, including the use of small organic molecules. Nerve growth factor (NGF) is used as a paradigmatic trophic factor, because of a wealth of evidence for its robust effects on working memory (i.e., a type of cognition that is severely impaired in AD); other trophic factors, discussed in the text, may also have the potential as drugs for this disorder. It is likely that a comprehensive approach to treat AD will involve multiple substances selective for particular pathogenetic events and nerve cell types.