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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 8

Viral-mediated Tau expression in the LC drives propagation of pathology to the forebrain in MAPT transgenic mice.

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Viral-mediated Tau expression in the LC drives propagation of pathology ...
LC-specific AAV-PRSx8-Tau + AAV-PRSx8-mCherry, or AAV-PRSx8-mCherry alone were injected into the LC of MAPT mice, and mice were assessed for Tau pathology throughout the brain by immunohistochemistry 3 months later. (A) Representative images of AT8 immunostaining throughout the brain of MAPT mice. (B) Representative images of immunofluorescent staining for TH (blue), AT8 or Tau N368 (green), and mCherry (red) in the LC of MAPT mice. Scale bar: 100 μm (top panels) and 20 μm (bottom panels). (C) Representative images of immunofluorescent staining for AT8 (green) or Tau N368 (red), and DAPI (blue) in the EC, HC, and frontal Cx of MAPT mice. Scale bar: 20 μm.
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