Asparagine endopeptidase cleaves tau at N167 after uptake into microglia
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Abstract
Tau cleavage by different proteolytic enzymes generates short, aggregation-prone fragments that have been implicated in the pathogenesis of Alzheimer's disease (AD). Asparagine endopeptidase (AEP) activity in particular has been associated with tau dysfunction and aggregation, and the activity of the protease is increased in both aging and AD. Using a mass spectrometry approach, we identified a novel tau cleavage site at N167 and confirmed its processing by AEP. In combination with the previously known site at N368, we show that AEP cleavage yields a tau fragment that is present in both control and AD brains at similar levels. AEP is a lysosomal enzyme, and our data suggest that it is expressed in microglia rather than in neurons. Accordingly, we observe tau cleavage at N167 and N368 after endocytotic uptake into microglia, but not neurons. However, tau 168-368 does not accumulate in microglia and we thus conclude that the fragment is part of a proteolytic cascade leading to tau degradation. While we confirm previous studies showing increased overall AEP activity in AD brains, our data suggests that AEP-mediated cleavage of tau is a physiological event occurring during microglial degradation of the secreted neuronal protein. As a consequence, we caution against preventing AEP-mediated tau cleavage as a therapeutic approach in AD.
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AEP cleaves tau without inducing tau accumulation in microglia.
“AEP cleaves tau without inducing tau accumulation in microglia.”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [213]
Tau can be cleaved by AEP at Asn167, Asn255, and Asn368.
“Tau can be cleaved by AEP at Asn167, Asn255, and Asn368 [212, 213].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [213]
AEP is predominately expressed in microglia.
“AEP is predominately expressed in microglia [135, 213]”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [213]
Truncated tau 1-368 (tau-368) generated by AEP cleavage exhibits impaired enhancement in microtubule assembly, and shows increased propensity to form PHFs in vitro.
“The truncated tau 1–368 (tau-368) isoform generated by AEP cleavage exhibits impaired enhancement in microtubule assembly, and shows increased propensity to form PHFs in vitro.”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [213]
AEP likely plays a role in regulating tau degradation, rather than enhancing tau aggregation.
“It is therefore likely that AEP plays a role in regulating tau degradation, rather than enhancing tau aggregation [212, 213, 215].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [213]
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Self-citation
- Authors
- Behrendt, A., Bichmann, M., Ercan-Herbst, E., Haberkant, P., Schöndorf, D. C., Wolf, M., Fahim, S. A., Murolo, E., & Ehrnhoefer, D. E.
- Affiliations
- BioMed X (DE)
- European Molecular Biology Laboratory (DE)
- Corresponding author
- Ehrnhoefer, Dagmar E.
- Venue
- Neurobiology of Disease
- Publisher
- Elsevier BV
- Published
- 2019-10
- Volume
- 130
- Pages
- 104518
- ISSN
- 0969-9961 (ISSN-L)
- OpenAlex
- W2953257368
- Cited by
- 26
- References
- 42
- Citations by year
- 2025: 3 · 2024: 4 · 2023: 5 · 2022: 3 · 2021: 7 · 2020: 3 · 2019: 1
- FWCI
- 2.56
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Locations
- Neurobiology of Disease (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- AbbVie Deutschland
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- asparaginyl endopeptidase, tau cleavage, Alzheimer's disease, microglia, lysosomal proteolysis, endocytosis, tau aggregation, tau degradation, therapeutic target
- MeSH terms
- Asparaginyl Endopeptidase, Brain, Cysteine Endopeptidases, Humans, Neurons, Mass Spectrometry, tau Proteins, Microglia, HEK293 Cells, Proteolysis
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