Evidence for decreased transport of PNMT protein in advanced Alzheimer's disease

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.