NEUROTROPHINS AND ALZHEIMERS-DISEASE - BEYOND THE CHOLINERGIC NEURONS

Improvement of the cholinergic deficit in Alzheimer's disease (AD) by intracerebral application of nerve growth factor (NGF) serves as a par adigmatic example for a novel approach to the treatment of neurodegene ration. The first part of this paper presents and discusses experiment s which were performed in our laboratory to study the NGF receptor res ponse after intracerebral NGF treatment in vivo. We found that intrapa renchymal NGF elicits prolonged tyrosine phosphorylation of Trk type N GF receptors. Our results indicate that intraparenchymal injections ar e preferable to intraventricular application for targeting specific ne uronal populations with minimal side effects. Besides the cholinergic deficit, severely disturbed brain energy metabolism, particularly in c ortical association areas, is another consistent feature of AD. Metabo lic hypofunction is observed early in the disease progression and corr elates with the cognitive impairment. Cell culture findings are presen ted which indicate that brain-derived neurotrophic factor (BDNF), and other neurotrophins with activity on the TrkB tyrosine kinase receptor , increase mRNA levels and biochemical activity of enzymes of the glyc olytic pathway in brain cells. Treatment with these factors was also f ound to stimulate glucose utilization in rat embryonic cortex cells in primary cultures. Our observations suggest that selected neurotrophin s should become useful not only for the treatment of the cholinergic d eficit in AD, but also of the cortical metabolic hypofunction associat ed with this disease.