The Norepinephrine Metabolite DOPEGAL Confers Locus Coeruleus Tau Vulnerability and Propagation via Asparagine Endopeptidase
Kang, S. S.; Liu, X.; Ahn, E. H.; Xiang, J.; Manfredsson, F. P.; Yang, X.; Luo, H. R.; Liles, L. C.; Weinshenker, D.; Ye, K.
Show abstract
Aberrant Tau inclusions in the locus coeruleus (LC) are the earliest detectable Alzheimers disease (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 (DOPEGAL), which is produced exclusively in noradrenergic neurons by monoamine oxidase A (MAO-A) metabolism of norepinephrine (NE), activates asparagine endopeptidase (AEP) that cleaves Tau at residue N368 into aggregation- and propagation-prone forms, thereby leading to LC degeneration and the spread of Tau pathology. DOPEGAL triggers AEP-cleaved Tau aggregation in vitro and in intact cells, resulting in LC neurotoxicity and propagation of pathology to the forebrain. Thus, our findings reveal a novel molecular mechanism underlying the selective vulnerability of LC neurons in AD.
Matching journals
The top 9 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- β-Amyloid Induces Microglial Expression of GPC4 and APOE Leading to Increased Neuronal Tau Pathology and Toxicity 96%
- APOE Christchurch enhances a disease-associated microglial response to plaque but suppresses response to tau pathology 96%
- Amyloid plaque deposition accelerates tau propagation via activation of microglia in a humanized APP mouse model 96%
Similar papers in this journal
- A peptide inhibitor of Tau-SH3 interactions ameliorates amyloid-β toxicity 97%
- Extracellular tau clearance is governed by its aggregation state and independent of microglial activation by LPS and IFN-γ 94%
- Tunable Tau Expression in C. elegans Neurons Reveals that Early-AD Tau Phosphorylation Selectively Impacts Behavior and Mitochondrial Quality Control 94%
Similar papers in this journal
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.