Evidence for Decreased Transport of PNMT Protein in Advanced Alzheimer's Disease

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Abstract
Phenylethanolamine N‐methyltransferase (PNMT) is the rate‐limiting enzyme in the synthesis of epinephrine and a specific marker for adrenergic neurons. PNMT protein is decreased in axon terminals in brains from patients with Alzheimer's disease due to retrograde degeneration of epinephrine neurons. To determine the subcellular mechanism underlying retrograde degeneration, the distribution of PNMT between axon terminal and cell body was calculated in early and advanced Alzheimer cases compared with age‐matched controls. In early Alzheimer's disease there is a decrease in PNMT in axon terminals and in total PNMT in epinephrine cell bodies and terminals compared with control values. There is no difference in the ratio of PNMT in cell body/axon terminal compared with controls. In contrast, in advanced Alzheimer's disease, PNMT activity increases by 124% in epinephrine neuronal cell bodies compared with controls. Immunochemical titration shows that this increased enzyme activity is due to an increase in PNMT protein. The cell body/axon terminal ratio of PNMT is increased 2.5‐fold in advanced Alzheimer's disease compared with controls. These findings are consistent with the hypothesis that in early Alzheimer's disease there is a decreased synthesis or increased degradation of PNMT. However, in advanced Alzheimer's disease we propose that the accumulation of this enzyme in the perikarya results from a diminished transport of PNMT to axon terminals. We further postulate that epinephrine, the product of PNMT, and its further metabolites are endogenous neurotoxins. Therefore, the accumulation of PNMT in epinephrine cell bodies may contribute to the degeneration of these neurons in Alzheimer's disease. A number of specific neurotransmitter systems undergo degeneration resulting in significant neuronal loss in Alzheimer's disease (AD). 1-6 Although the end stage of the degenerative process may be cell loss, a number of structural and chemical changes, including atrophy, occur before cell loss. However, little is known about the cellular and subcellular mechanisms involved in the degenerative process. Interference with axonal transport of neurofilament protein in neurons may be the pathogenetic mechanism in AD. 7 Iqbal 8 showed a defect in assembly of microtubules in AD that plays a role in axonal transport. Recently, impaired axonal transport of choline acetyltransferase (CHAT) in the nucleus basalis of patients with advanced, but not early, AD was reported. 9 Investigations suggest that a defect in transport of protein is a cause for nerve cell death. 10 However, underlying biochemical mechanisms by which decreased axonal transport results in neuronal death have not been described. Phenylethanolamine N‐methyltransferase (PNMT) is the rate‐limiting enzyme in epinephrine (Epi) synthesis 11 and the specific enzymatic marker for the Epi neurotransmitter system. This transmitter system has cell bodies in the brainstem 12 , 13 that project to both cortical and subcortical regions of the brain. 2 , 14 One of the major projections of the Epi neurons is to the locus ceruleus, which receives 84% of its Epi projection from C‐1 neurons in the rostral ventral lateral medulla. 15 , 16 The Epi neurons are important to study in AD because, although there is structural evidence of degeneration in the nerve cell bodies, including ballooning and atrophy, there is no loss of cell bodies even in severely affected AD cases. 17 , 18 We have shown that in AD brains PNMT protein is decreased in projection areas affected by the disease. 2 , 17 Chemical and structural changes in Epi neurons related to the loss of postsynaptic locus ceruleus neurons in AD led us to postulate that the cellular degeneration is retrograde. 18 The biochemical mechanisms that lead to secondary retrograde degeneration of Epi neurons are unknown. The purpose of the present study is to determine whether decreased axonal transport underlies secondary degeneration of neurons. This goal was accomplished by: (1) measuring the amount of PNMT activity and protein in Epi neuronal cell bodies and axon terminals in early and advanced AD compared with control brains; (2) determining the distribution of PNMT between cell bodies and axon terminals in early and advanced AD compared with controls; and (3) determining the relationship between decreased PNMT transport in C‐1 neurons and loss of postsynaptic neurons. In addition, we suggest how the accumulation of PNMT could be toxic to Epi neurons.