Title

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

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