Norepinephrine metabolite DOPEGAL activates AEP and pathological Tau aggregation in locus coeruleus.
Department
Neurobiology
Document Type
Article
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.
Publication Date
1-2-2020
Publication Title
The Journal of clinical investigation
ISSN
1558-8238
Volume
130
Issue
1
First Page
422
Last Page
437
PubMed ID
31793911
Digital Object Identifier (DOI)
10.1172/JCI130513
Recommended Citation
Kang, Seong Su; Liu, Xia; Ahn, Eun Hee; Xiang, Jie; Manfredsson, Fredric P; Yang, Xifei; Luo, Hongbo R; Liles, L Cameron; Weinshenker, David; and Ye, Keqiang, "Norepinephrine metabolite DOPEGAL activates AEP and pathological Tau aggregation in locus coeruleus." (2020). Translational Neuroscience. 485.
https://scholar.barrowneuro.org/neurobiology/485