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Cited by 33Heat shock proteins researchAlzheimer's disease research and treatmentsAutophagy in Disease and Therapy

Alzheimer Cells on Their Way to Derailment Show Selective Changes in Protein Quality Control Network

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Koopman, Margreet B., Rüdiger, Stefan G. D.·2020·Frontiers in Molecular Biosciences
DOI 10.3389/fmolb.2020.00214PMC PMC7715003

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Abstract

Alzheimer’s Disease is driven by protein aggregation and is characterized by accumulation of Tau protein into neurofibrillary tangles. In healthy neurons the cellular protein quality control is successfully in charge of protein folding, which raises the question to which extent this control is disturbed in disease. Here, we describe that brain cells in Alzheimer’s Disease show very specific derailment of the protein quality control network. We performed a meta-analysis on the Alzheimer’s Disease Proteome database, which provides a quantitative assessment of disease-related proteome changes in six brain regions in comparison to age-matched controls. We noted that levels of all paralogs of the conserved Hsp90 chaperone family are reduced, while most other chaperones – or their regulatory co-chaperones - do not change in disease. The notable exception is a select group consisting of the stress inducible HSP70, its nucleotide exchange factor BAG3 – which links the Hsp70 system to autophagy - and neuronal small heat shock proteins, which are upregulated in disease. They are all members of a cascade controlled in the stress response, channeling proteins towards a pathway of chaperone assisted selective autophagy. Together, our analysis reveals that in an Alzheimer’s brain, with exception of Hsp90, the players of the protein quality control are still present in full strength, even in brain regions most severely affected in disease. The specific upregulation of small heat shock proteins and HSP70:BAG3, ubiquitous in all brain areas analyzed, may represent a last, unsuccessful attempt to advert cell death.

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  • Hspa4 maintained the disaggregating property of misfolded proteins, thereby preventing further damage and inducing tissue integrity.

    “Amongst the heat shock proteins, we found Hspa4 to be upregulated which ensured that it maintained the disaggregating property of any misfolded proteins, thereby, preventing further damage and inducing tissue integrity89.”

    From Chlamydia pneumoniae can infect the central nervous system via the olfactory and trigeminal nerves and contributes to Alzheimer’s disease risk (2022) · cites this paper as [89]

    The Results section, “HSP70 Efflux Derails Toward Autophagy” (page unavailable), identifies HSPA4 as contributing to Hsp70-mediated disaggregation but explicitly says its levels remained unaffected in Alzheimer’s brains—not upregulated. It does not report that HSPA4 prevented further damage or improved tissue integrity. (LLM, conf=0.88)

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Authors
Koopman, M. B., & Rüdiger, S. G. D.
Affiliations
Utrecht University (NL)
Corresponding author
  • Koopman, Margreet B.
  • Rüdiger, Stefan G. D.
ORCID
Venue
Frontiers in Molecular Biosciences
Publisher
Frontiers Media SA
Published
2020-11-20
Volume
7
Pages
214-214
ISSN
2296-889X (ISSN-L)
DOI
10.3389/fmolb.2020.00214
PMC
PMC7715003
OpenAlex
W3109321415
Cited by
33
References
6
Citations by year
2026: 3 · 2025: 7 · 2024: 6 · 2023: 4 · 2022: 7 · 2021: 5 · 2020: 1
FWCI
1.37
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Molecular Biosciences (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
Funders
ZonMw
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
Keywords
Alzheimer's disease, protein quality control, HSP90, HSP70, BAG3, small heat shock proteins, molecular chaperones, selective autophagy, protein aggregation, neurofibrillary tangles, tau protein, stress response, proteome changes, brain regions, neuroprotection

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