Anti-Aβ Antibody Aducanumab Regulates the Proteome of Senile Plaques and Closely Surrounding Tissue in a Transgenic Mouse Model of Alzheimer’s Disease
Abstract
Background: Alzheimer’s disease (AD) is characterized by accumulation of amyloid-β (Aβ) species and deposition of senile plaques (SPs). Clinical trials with the anti-Aβ antibody aducanumab have been completed recently. Objective: To characterize the proteomic profile of SPs and surrounding tissue in a mouse model of AD in 10-month-old tgAPPPS1-21 mice after chronic treatment with aducanumab for four months with weekly dosing (10 mg/kg). Methods: After observing significant reduction of SP numbers in hippocampi of aducanumab-treated mice, we applied a localized proteomic analysis by combining laser microdissection and liquid chromatography-tandem mass spectrometry (LC-MS/MS) of the remaining SPs in hippocampi. We microdissected three subregions, containing SPs, SP penumbra level 1, and an additional penumbra level 2 to follow the proteomic profile as gradient. Results: In the aducanumab-treated mice, we identified 17 significantly regulated proteins that were associated with 1) mitochondria and metabolism (ACAT2, ATP5J, ETFA, EXOG, HK1, NDUFA4, NDUFS7, PLCB1, PPP2R4), 2) cytoskeleton and axons (ADD1, CAPZB, DPYSL3, MAG), 3) stress response (HIST1H1C/HIST1H1D, HSPA12A), and 4) AβPP trafficking/processing (CD81, GDI2). These pathways and some of the identified proteins are implicated in AD pathogenesis. Proteins associated with mitochondria and metabolism were mainly upregulated while proteins associated with AβPP trafficking/processing and stress response pathways were mainly downregulated, suggesting that aducanumab could lead to a beneficial proteomic profile around SPs in tgAPPPS1-21 mice. Conclusion: We identified novel proteomic patterns of SPs and surrounding tissue indicating that chronic treatment with aducanumab could inhibit Aβ toxicity and increase phagocytosis and cell viability.
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NDUFA4 has been identified as one of the few significantly regulated proteins in Aβ plaques in anti-Aβ antibody aducanumab treated transgenic mice, suggesting that upregulation of NDUFA4 in plaques may inhibit Aβ toxicity and increase phagocytosis and cell viability.
“NDUFA4, that codes for a mitochondrial protein has been identified as one of the few significantly regulated proteins in Aβ plaques in anti-Aβ antibody aducanumab treated transgenic mice, suggesting that upregulation of NDUFA4 in plaques may inhibit Aβ toxicity and increase phagocytosis and cell viability [47].”
From Genome-wide analysis identifies novel loci influencing plasma apolipoprotein E concentration and Alzheimer’s disease risk (2023) · cites this paper as [47]
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- Authors
- Bastrup, J., Hansen, K. H., Poulsen, T. B. G., Kastaniegaard, K., Asuni, A. A., Christensen, S., Belling, D., Helboe, L., Stensballe, A., & Volbracht, C.
- Affiliations
- Lundbeck (Denmark) (DK)
- Aalborg University (DK)
- Biogenity, Aalborg, Denmark
- Corresponding author
- Volbracht, Christiane
- ORCID
- Venue
- Journal of Alzheimer's Disease
- Publisher
- SAGE Publications
- Published
- 2021-01-05
- Volume
- 79
- Issue
- 1
- Pages
- 249-265
- ISSN
- 1387-2877 (ISSN-L)
- 1875-8908
- OpenAlex
- W3110354915
- Cited by
- 46
- References
- 5
- Citations by year
- 2026: 5 · 2025: 9 · 2024: 8 · 2023: 4 · 2022: 14 · 2021: 5 · 2013: 1
- FWCI
- 3.45
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Alzheimer s Disease (publishedVersion)
- PubMed (publishedVersion)
- VBN Forskningsportal (Aalborg Universitet) (submittedVersion)
- 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
- aducanumab, anti-amyloid beta antibodies
- MeSH terms
- Alzheimer Disease, Animals, Brain, Chromatography, Liquid, Cytoskeletal Proteins, Disease Models, Animal, Humans, Mice, Transgenic, Stress, Physiological, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Proteome, Protein Transport, Mitochondrial Proteins, Proteomics, Mice, Tandem Mass Spectrometry, Presenilin-1, Plaque, Amyloid, Antibodies, Monoclonal, Humanized
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