NERVE GROWTH-FACTOR POTENTIATES THE NEUROTOXICITY OF BETA-AMYLOID

The role of growth factors in the pathogenesis of Alzheimer disease is unknown. The β-amyloid protein accumulates abnormally in the brain in Alzheimer disease and is neurotoxic to differentiated hippocampal neurons in culture. Nerve growth factor (NGF) increased the neurotoxic potency of a β-amyloid polypeptide by a factor of ≃100,000, which resulted in a reduction of the β-amyloid neurotoxic EC50 from 0.1 μM to 1 pM. This potentiating effect of NGF was reversed by a monoclonal antibody against NGF and was not observed for a variety of other neurotrophic growth factors. Exposure of hippocampal neurons to very low concentrations of β amyloid alone resulted in a marked induction of immunoreactive NGF receptors. Addition of NGF with β amyloid resulted in the appearance of neurodegenerative changes in NGF receptor-positive neurons. The early and profound degeneration of hippocampal and basal forebrain cholinergic neurons that occurs in Alzheimer disease may result from a neurotoxic interaction of β amyloid with NGF.