NGF and the treatment of Alzheimer's disease.

Issues related to the possible treatment of Alzheimer's disease with nerve growth factor (NGF) are discussed. Animal research has demonstrated that the ascending cholinergic projections in the brain express low- and high-affinity receptors for NGF and are NGF-sensitive as well as probably NGF-dependent. Cholinergic lesions lead to cognitive disturbances, and treatment with NGF can improve cognitive behavior in animals. It thus seems reasonable to attempt to counteract the degeneration of cholinergic systems known to occur in patients with Alzheimer's disease by treatment with NGF. There are several different possible ways of stimulating NGF receptors such as NGF infusion, implantation of slow-release biodegradable pellets, using carrier-mediated transport across the blood-brain barrier, grafting NGF-producing cells, transferring genes directly to the brain, developing NGF receptor agonists, or controlling the endogenous NGF production. The first clinical trial of NGF infusion is described in some detail. Based on background information from intracerebral infusion of NGF in parkinsonian patients, attempting to support intraputaminal chromaffin tissue grafts, a study was initiated using a radio-controlled fully implantable pumping device delivering NGF to the lateral ventricle. Several transient or more long-lasting "improvements" were noted in the pilot case. These involved increases of blood flow and nicotine binding as evaluated by positron-emission tomography as well as improvement of the EEG and certain psychological tests, tapping verbal episodic memory. Negative effects of NGF or formation of antibodies against NGF were not noted. In discussing the pilot case, the one conclusion which appears warranted is that it is reasonable to continue the clinical research with NGF treatment of a low number of patients with Alzheimer's disease. The question of whether neurotrophin-mediated mechanisms are disturbed in Alzheimer's disease is discussed. While this issue cannot be settled at present, it is argued that NGF can be used as a pharmacological agent, whether or not there are any primary disturbances of neurotrophin-mediated mechanisms in Alzheimer's disease. Finally, the possibility that NGF might have other positive or negative effects is discussed. In particular, the increase in blood flow noted in the Alzheimer patient suggests that data from clinical research may also generate a feedback to basic science, thus aiding in attempts to find new treatment strategies for neurodegenerative diseases.