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Norepinephrine metabolite DOPEGAL activates AEP and pathological Tau aggregation in locus coeruleus
Seong Su Kang, … , David Weinshenker, Keqiang Ye
Seong Su Kang, … , David Weinshenker, Keqiang Ye
Published December 3, 2019
Citation Information: J Clin Invest. 2020;130(1):422-437. https://doi.org/10.1172/JCI130513.
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Research Article Cell biology Neuroscience

Norepinephrine metabolite DOPEGAL activates AEP and pathological Tau aggregation in locus coeruleus

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Abstract

Aberrant Tau inclusions in the locus coeruleus (LC) are the earliest detectable Alzheimer’s disease–like (AD-like) neuropathology in the human brain. However, why LC neurons are selectively vulnerable to developing early Tau pathology and degenerating later in disease and whether the LC might seed the stereotypical spread of Tau pathology to the rest of the brain remain unclear. Here, we show that 3,4-dihydroxyphenylglycolaldehyde, which is produced exclusively in noradrenergic neurons by monoamine oxidase A metabolism of norepinephrine, activated asparagine endopeptidase that cleaved Tau at residue N368 into aggregation- and propagation-prone forms, thus leading to LC degeneration and the spread of Tau pathology. Activation of asparagine endopeptidase–cleaved Tau aggregation in vitro and in intact cells was triggered by 3,4-dihydroxyphenylglycolaldehyde, resulting in LC neurotoxicity and propagation of pathology to the forebrain. Thus, our findings reveal that norepinephrine metabolism and Tau cleavage represent the specific molecular mechanism underlying the selective vulnerability of LC neurons in AD.

Authors

Seong Su Kang, Xia Liu, Eun Hee Ahn, Jie Xiang, Fredric P. Manfredsson, Xifei Yang, Hongbo R. Luo, L. Cameron Liles, David Weinshenker, Keqiang Ye

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Figure 12

A model for the selective vulnerability by DA or NE metabolites, monoamine oxidase, and AEP in PD and AD.

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A model for the selective vulnerability by DA or NE metabolites, monoami...
DOPAL, which is a DA metabolite by MAO-B, has a toxic effect in the substantia nigra in the progression of PD by mediating AEP activation and α-synuclein toxicity. Similarly, MAO-A and its toxic metabolite of NE, DOPEGAL, induce Tau toxicity in noradrenergic cells of LC in the early stage of AD progression.
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