The role of copper and the copper-related protein CUTA in mediating APP processing and Aβ generation
Abstract
One major pathologic hallmark and trigger of Alzheimer's disease (AD) is overproduction and accumulation of β-amyloid (Aβ) species in the brain. Aβ is derived from β-amyloid precursor protein (APP) through sequential cleavages by β- and γ-secretases. Abnormal copper homeostasis also contributes to AD pathogenesis. Recently, we find that a copper-related protein, CutA divalent cation tolerance homolog of Escherichia coli (CUTA), interacts with the β-secretase β-site APP cleaving enzyme 1 (BACE1) and inhibits APP β-processing and Aβ generation. Herein, we further found that overexpression of CUTA increases intracellular copper level, whereas copper treatments promote CUTA expression. We also confirmed that copper treatments promote APP expression and Aβ secretion. In addition, copper treatments promoted the increase of Aβ secretion induced by CUTA downregulation but had no effect on CUTA-β-site APP cleaving enzyme 1 interaction. On the other hand, CUTA overexpression ameliorated copper-induced Aβ secretion but had no effect on APP expression. Moreover, we found that Aβ treatments can reduce both CUTA and copper levels in mouse primary neurons. Consistently, both CUTA and copper levels were decreased in the hippocampus of APP/PS1 AD mouse brain. Together, our results reveal a reciprocal modulation of copper and CUTA and suggest that both regulate Aβ generation through different mechanisms, although Aβ mutually affects copper and CUTA levels.
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CUTA modulates the generation of β-amyloid peptides (Aβ), major components of senile plaques typical of Alzheimer's disease.
“CUTA also modulates the generation of β-amyloid peptides (Aβ), major components of senile plaques typical of Alzheimer’s disease93.”
From Distinct selective forces and Neanderthal introgression shaped genetic diversity at genes involved in neurodevelopmental disorders (2017) · cites this paper as [93]
The longest isoform of CUTA interacts with BACE1, a β-secretase involved in generation of Aβ peptides, reducing secretion of neurotoxic molecules.
“Specifically, the longest isoform of CUTA interacts with BACE1, a β-secretase involved in the generation of Aβ peptides, reducing secretion of neurotoxic molecules.”
From Distinct selective forces and Neanderthal introgression shaped genetic diversity at genes involved in neurodevelopmental disorders (2017) · cites this paper as [93]
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- Authors
- Hou, P., Liu, G., Zhao, Y., Shi, Z., Zheng, Q., Bu, G., Xu, H., & Zhang, Y.-W.
- Affiliations
- Xiamen University (CN)
- Sanford Burnham Prebys Medical Discovery Institute (US)
- Corresponding author
- Zhang, Yun-wu
- Venue
- Neurobiology of Aging
- Publisher
- Elsevier BV
- Published
- 2015-03
- Volume
- 36
- Issue
- 3
- Pages
- 1310-1315
- ISSN
- 0197-4580 (ISSN-L)
- OpenAlex
- W2048982025
- Cited by
- 32
- References
- 29
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 1 · 2023: 2 · 2022: 2 · 2021: 5 · 2020: 4 · 2019: 2 · 2018: 2 · 2017: 3 · 2016: 6
- FWCI
- 2.00
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neurobiology of Aging (publishedVersion)
- PubMed (publishedVersion)
- Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
- Funders
- National Natural Science Foundation of China (81225008, 81161120496, 91332112, 91332114)
- Fundamental Research Funds (2012121048)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Nursing › Nutrition and Dietetics › Trace Elements in Health
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- copper, copper homeostasis, APP processing, BACE1, Alzheimer's disease, APP/PS1 mice, hippocampus
- MeSH terms
- Alzheimer Disease, Animals, Cells, Cultured, Copper, Homeostasis, Humans, Membrane Proteins, Mice, Inbred C57BL, Rabbits, Gene Expression, Amyloid beta-Peptides, Aspartic Acid Endopeptidases, Amyloid beta-Protein Precursor, Amyloid Precursor Protein Secretases
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