Adrenergic Receptors in Aging and Alzheimer's Disease: Increased β2‐Receptors in Prefrontal Cortex and Hippocampus

Abstract

Loss of pigmented noradrenergic locus ceruleus neurons occurs in Alzheimer's disease (AD) and, to a lesser extent, in aging. We studied beta-adrenergic receptors and their subtypes, beta 1 and beta 2, by the specific binding of 125I-pindolol to particulate membrane preparations from prefrontal cortex, hippocampus, putamen, and cerebellum and to sections from frontal cortex by in vitro autoradiography. In prefrontal cortex from controls, numbers of total beta- and beta 2-adrenoceptors did not significantly correlate with age, but number of beta 1-adrenoceptors showed a weak but significant negative correlation. Binding in tissue particulate preparations to total beta-receptors did not reveal significant differences in samples from prefrontal cortex between AD subjects and age-matched controls. However, beta 1-adrenoceptors were decreased and beta 2-adrenoceptors were increased in number by approximately 30-50% in AD subjects. Thus, the relative ratio of beta 1-/beta 2-receptors was decreased in AD. Binding by in vitro receptor autoradiography performed in a subset of samples of frontal cortex also showed beta 2-adrenoceptors, and less consistently total beta- and beta 1-receptors, to be increased significantly in number in cortical laminae II, III, IV, and V of tissue sections from AD subjects. In these subjects, number of locus ceruleus cells and norepinephrine concentrations in putamen and frontal cortex were markedly reduced compared with values in controls. In the hippocampus, total beta- and both beta 2- and beta 1-adrenoceptors were increased in number in AD. In contrast, in the putamen, where beta 1-receptors predominate, total beta- and beta 1-receptors were significantly decreased in number with no consistent change in content of beta 2-receptors in AD. There were no significant changes in the cerebellum. Specific pindolol binding was not affected by interval between death and sampling of tissue at autopsy. Our results indicate selective changes in number of beta-receptors in AD. These changes in the cortex and hippocampus suggest receptor upregulation in response to noradrenergic deafferentation from the locus ceruleus or may simply reflect glial proliferation in AD.