Does loss of nerve growth factor receptors precede loss of cholinergic neurons in Alzheimer's disease? An autoradiographic study in the human striatum and basal forebrain

Abstract

The mechanism by which cholinergic neurons degenerate in Alzheimer's disease is not known. Some of these neurons depend, however, on trophic support from NGF via a membrane receptor. We have analyzed the state of these receptors by autoradiography, with 125I-NGF as the ligand, in the caudate nucleus, putamen, ventral striatum, nucleus basalis of Meynert, and nucleus tegmenti pedunculopontinus of six patients with Alzheimer's disease and five controls, matched for age and postmortem delay. The binding characteristics were similar in the striatum (including caudate nucleus, putamen, and ventral striatum) and basal forebrain of control subjects and patients with Alzheimer's disease (Kd = 2.5-4 x 10(-11) M). In control brains, high levels of 125I-NGF binding were observed in the basal forebrain and striatum (0.32-0.49 fmol/mg tissue equivalent), but no specific binding was detected in the nucleus tegmenti pedunculopontinus. NGF binding sites were distributed heterogeneously in the striatum with patches of low density, corresponding to AChE-poor striosomes, surrounded by a matrix in which receptor density was significantly greater. In Alzheimer's disease, the density of NGF receptors was markedly decreased in the caudate nucleus, putamen, ventral striatum, and nucleus basalis of Meynert. In contrast, AChE staining decreased less in the nucleus basalis of Meynert in all Alzheimer's disease patients, and in the ventral striatum of those most severely affected. These results indicate that if NGF receptors are located on cholinergic neurons, receptor loss and the consequent decrease in trophic support may precede cell degeneration in Alzheimer's disease. The relationship between the loss of these receptors and the pathogenesis of the disease remains to be determined.