期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 130, 期 1, 页码 422-437出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI130513
关键词
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资金
- NIH [R01AG051538, RF1 AG061175, RF1AG047667]
- University of Washington Alzheimer's Disease Research Center [NIH P50AG005136]
- Kaiser Permanente Adult Changes in Thought Study [NIH U01 AG006781]
- Rodent Behavioral Core (RBC)
- Viral Vector Core - Emory University School of Medicine
- Emory Neuroscience NINDS Core Facilities [P30NS055077]
- Georgia Clinical & Translational Science Alliance of the NIH [UL1TR002378]
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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