This letter is in response to the editorial by Rye and DeLong1 and the accompanying article by Zarow et al.2 Our research has focused on the locus ceruleus for many years. We have detailed the mechanism of death of locus ceruleus neurons in Alzheimer disease as follows. We demonstrated that the monoamine oxidase type A metabolite of norepinephrine (NE), 3,4-dihydroxyphenylglycolaldehyde (DOPEGAL), is highly toxic and triggers apoptotic neuron death in in vitro and in vivo models of adrenergic neurons.3- 5 Neither NE nor its other metabolites were toxic in these models. We showed that DOPEGAL but not NE generates free radicals, induces mitochondria permeability transition, and activates caspases.6,7 These mechanisms underlie apoptotic neuron death.8 We also showed that NE, DOPEGAL, and their synthesizing enzymes accumulate in the locus ceruleus neurons in Alzheimer disease.9 We postulated that the accumulation of DOPEGAL in these neurons is due to defective axonal transport caused by phosphorylation of tau protein, which interferes with assembly of the microtubule transport system. Phosphorylation of tau is triggered by β-amyloid, a protein genetically linked to Alzheimer disease.10 Alternately, toxic aggregates of β-amyloid, like α-synuclein aggregates, could permeabilize NE storage vesicles.11,12 This would allow NE to leak into the cytosol, where it is converted to DOPEGAL. This is perhaps the most complete explanation of the mechanisms underlying neuron death in Alzheimer disease to date.
Burke WJ. Focus on the Locus. Arch Neurol. 2003;60(10):1493. doi:10.1001/archneur.60.10.1493-a