한빛사 논문
Seong Su Kang,1 Xia Liu,1 Eun Hee Ahn,1 Jie Xiang,1 Fredric P. Manfredsson,2 Xifei Yang,3 Hongbo R. Luo,4 L. Cameron Liles,5 David Weinshenker,5 and Keqiang Ye1,*
1 Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.
2 Translational Science and Molecular Medicine, Michigan State University, College of Human Medicine, Grand Rapids, Michigan, USA.
3 Key Laboratory of Modern Toxicology of Shenzhen, Shenzhen Center for Disease Control and Prevention, Shenzhen, China.
4 Department of Pathology and Laboratory Medicine, Harvard Medical School and Children’s Hospital, Boston, Massachusetts, USA.
5 Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia, USA.
*Address correspondence to: Keqiang Ye, 615 Michael Street, Whitehead Bldg, Room #141, Atlanta, Georgia 30322, USA.
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.
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