DECREASED TRKA GENE-EXPRESSION IN CHOLINERGIC NEURONS OF THE STRIATUMAND BASAL FOREBRAIN OF PATIENTS WITH ALZHEIMERS-DISEASE

In addition to cortical pathology, Alzheimer's disease is characterize d by a loss of cholinergic neurons in the basal forebrain and the vent ral striatum. Since cholinergic neurons which degenerate in Alzheimer' s disease are sensitive to nerve growth factor, a link between nerve g rowth factor sensitivity and the vulnerability of cholinergic neurons has been suspected. The purpose of this study was to determine, in cho linergic neurons, the level of expression of TrkA, the high affinity r eceptor for nerve growth factor, in control subjects and Alzheimer pat ients. The study was performed by in situ hybridization using a S-35-l abeled RNA probe complementary to human TrkA mRNA on immunohistochemic ally identified cholinergic neurons of the nucleus basalis of Meynert, the ventral striatum, and the putamen in postmortem brains of patient s with clinically and neuropathologically confirmed Alzheimer's diseas e and control subjects. In patients with Alzheimer's disease, a decrea se in TrkA mRNA expression was observed in the nucleus basalis of Meyn ert (-75%, P < 0.001) and the ventral striatum (-41%, P < 0.01), where the cholinergic neurons degenerate, and also in the anterior (-43%, P < 0.01) and posterior (-51%, P < 0.01) parts of the putamen, where th ey are spared but display precocious signs of cell alterations. These results, taken in conjunction with the reduced choline acetyltransfera se activity and our previously published data showing a loss of high a ffinity nerve growth factor binding in both the dorsal and the ventral striatum of patients with Alzheimer's disease, indicate that receptor loss and the consequent decrease in trophic support may be associated with the degeneration of cholinergic neurons during Alzheimer's disea se. (C) 1997 Academic Press.