Trk neurotrophin receptors in cholinergic neurons of patients with Alzheimer's disease

Besides cortical pathology, Alzheimer's disease (AD) is characterized by a loss of cholinergic neurons in the basal forebrain but not in the caudate nucleus, putamen or mesencephalon. Since cholinergic neurons which degenerate in AD are sensitive to nerve growth factor (NGF), a link between NGF sensitivity and the vulnerability of cholinergic neurons has been suspected. Levels of NGF are not altered in patients with AD, however. Thus, cholinergic nerve cell death in AD could result from a deficiency in NGF receptors. Using sequential immunohistochemistry with antibodies that recognize preferentially TrkA, the specific receptor for NGF, and with antibodies directed against choline acetyltransferase we analyzed the expression of neurotrophin receptors in cholinergic neurons from control and AD brains. TrkA was expressed on cholinergic neurons of the striatum and nucleus basalis of Meynert but not on those of the mesencephalon. In AD patients, the number of neurons expressing TrkA was markedly decreased in the nucleus basalis of Meynert, very likely as a consequence of cholinergic neuronal loss. No loss of TrkA-positive neurons was observed in the striatum. Taken in conjunction with our previously published report of loss of high-affinity NGF binding in the striatum of AD patients, our results suggest a reduced expression of TrkA, the specific receptor for NGF, on striatal cholinergic neurons in AD. The loss of neurotrophin receptors may contribute to the alteration of cholinergic neurons occurring in AD.