NSMB Ye Keqiang/Zhang Zhentao collaborated to reveal the mechanism of Tau protein aggregation and lesion dissemination in the locus coeruleus region

Editor-in-Chief | XI Alzheimer's disease (AD) is the most common neurodegenerative disease in clinical practice, and abnormal aggregation of tau protein in the brain is an important pathological manifestation of AD
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But so far, the molecular mechanism of abnormal aggregation of tau protein remains unclear
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Pathological studies have found that the locus coeruleus is one of the initiation sites of Tau protein aggregation in the brain.
Tau protein first forms pathological aggregates in the locus coeruleus and spreads to other brain regions, resulting in extensive Tau protein aggregation in the brain and neural damage, eventually leading to cognitive impairment
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So, why is the Tau protein in the locus coeruleus more prone to aggregation? On March 24, 2022, Ye Keqiang's team from Shenzhen University of Technology and Zhang Zhentao's team from Renmin Hospital of Wuhan University published an article Tau modification by the norepinephrine metabolite DOPEGAL stimulates its pathology and propagation in Nature Structural & Molecular Biology
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The research team found that the norepinephrine metabolite DOPEGAL in the locus coeruleus covalently modifies the K353 site of Tau protein, promoting Tau aggregation and disease dissemination
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This study provides a new perspective for exploring the pathogenesis of Alzheimer's disease
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The research team has conducted a long-term exploration of the molecular mechanism of Tau protein aggregation in the brain
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The team's previous research found that monoamine oxidase A (MAO-A) at the locus coeruleus oxidizes norepinephrine to DOPAGEL, which activates the expression of asparagine endopeptidase (AEP), which cleaves Tau protein and promotes its aggregation and seeding.
(Journal of Clinical Investigation, 2020)
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Figure 1.
DOPAGEL promotes intracellular Tau aggregation, while the K353R mutation can block DOPEGAL's promotion.
Next, the team found that ApoE3 binds to Tau, reducing the cleavage of Tau by AEP, but the AD-associated allele, ApoE4, is lost The ability to bind Tau protein makes Tau more easily cleaved by AEP
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On the other hand, ApoE4 can inhibit the level of the vesicular monoamine transporter VMAT, making it difficult for norepinephrine to enter synaptic vesicles, while remaining in the cytoplasm is oxidized by MAO-A to generate DOPAGEL (Acta Neuropathologica, 2021)
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In the work of NSMB, the team further studied the modification effect of DOPAGEL on Tau and found that DOPAGEL can directly covalently modify the K353 site of Tau.
Compared with full-length Tau, the Tau protein fragment formed by AEP cleavage is easier Modified by DOPAGEL
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The Tau protein modified by DOPAGEL has stronger aggregation ability, and the formed pathological aggregates act as "seeds" to induce the aggregation ability of Tau protein monomers
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Blocking the activity of MAO-A in the brain of Tau transgenic mice, or mutating the K353 site of Tau can block the modification of Tau by DOPAGEL, and partially alleviate the spread of Tau lesions
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Figure 2.
Blocking DOPEGAL modification of Tau can delay Tau aggregation
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Intracerebral injection of Tau aggregates into the brain of Tau-overexpressing transgenic mice can induce Tau aggregation in the brain, and mutation of the K3533 site blocks the modification of Tau by DOPEGAL, and the aggregation of Tau in the brain is reduced.
The significance of this study is to reveal In the pathogenesis of AD, why Tau protein in the locus coeruleus first aggregates to form pathological inclusion bodies has a very important enlightenment role in understanding the initiation and dissemination of Tau protein aggregates in the brain of AD patients
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In this way, the inhibition of MAO-A with small molecule drugs in the early stage of AD disease may greatly slow down the pathological changes of Tau
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However, whether the discovery of this new mechanism can also be extended to other Tauopathies diseases associated with tau pathological changes requires further experimental verification
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Original link: https://doi.
org/10.
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