Degeneration of the cholinergic innervation of the locus ceruleus in Alzheimer's disease

Abstract

Choline acetyltransferase (Acetyl-CoA: choline O-acetyltransferase: EC 2.3.1.6) (ChAT) enzyme activity and neuron density were measured in the locus ceruleus (LC) of autopsied brains of neurologically normal individuals and patients who had Alzheimer's disease. Neuron density in the LC of individuals with Alzheimer's was significantly reduced to approximately 50% of normal values. ChAT activity was also reduced by about 50%. Furthermore, the number of pigmented neurons in the LC was highly correlated with presynaptic ChAT activity. These findings were specific for the LC, since deficits in ChAT and neuron density were not found in two adrenergic brainstem nuclei (C1 and C2). We measured mitogen activity in LC extracts in order to determine whether loss of cholinergic afferents to the LC, as evidenced by loss of ChAT, was related to putative trophic factors. Mitogen activity was significantly reduced (50%) in the Alzheimer's group as compared to normals. Mitogen activity was significantly correlated with ChAT activity and the density of neurons in the LC. The loss of cholinergic nerve terminals in the LC in Alzheimer's disease may be functionally significant, since acetylcholine has important effects on LC physiology. The highly significant relationships between ChAT, neuron density and mitogen activity has important implications for our understanding of mechanisms of neurodegeneration in Alzheimer's disease.