Neurotrophic mechanisms and neuronal degeneration

Dysfunction of neurotrophic mechanisms represents an important possible cause of neurodegeneration. Basal forebrain cholinergic neurons provide a useful model system in which to investigate this possibility since these neurons atrophy and degenerate in aging and Alzheimer's disease, and bear receptors to the neurotrophins NGF and BDNF. Neuropathologic evidence to date suggests that production of neurotrophins is not substantially decreased in aging or Alzheimer's disease, and experimental studies show that decreased access to targetderived neurotrophin may cause neuronal atrophy but is not lethal to mature basal forebrain cholinergic neurons. In aged rats, basal forebrain cholinergic neurons show a substantial decline in their capacity to take up and retrogradely transport ¹²⁵I-labelled NGF from their target region, and neurons not transporting labelled NGF appear severely atrophic. These changes are accompanied by a pronounced reduction in basal forebrain levels of mRNA encoding the high affinity NGF receptor. Together these findings suggest that while reduced levels of target-derived neurotrophin may not be a major factor in causing neuronal cell death they may contribute to atrophic neurodegenerative changes. In addition, intrinsic changes such as an age-related reduction in the capacity to sustain receptor mediated uptake and retrograde transport of target-derived neurotrophins may render certain neurons more vulnerable to neurodegeneration.