Differences in amyloid-β clearance across mouse and human blood–brain barrier models: Kinetic analysis and mechanistic modeling
Open accessAbstract
Alzheimer's disease (AD) has a characteristic hallmark of amyloid-β (Aβ) accumulation in the brain. This accumulation of Aβ has been related to its faulty cerebral clearance. Indeed, preclinical studies that used mice to investigate Aβ clearance showed that efflux across blood-brain barrier (BBB) and brain degradation mediate efficient Aβ clearance. However, the contribution of each process to Aβ clearance remains unclear. Moreover, it is still uncertain how species differences between mouse and human could affect Aβ clearance. Here, a modified form of the brain efflux index method was used to estimate the contribution of BBB and brain degradation to Aβ clearance from the brain of wild type mice. We estimated that 62% of intracerebrally injected (125)I-Aβ40 is cleared across BBB while 38% is cleared by brain degradation. Furthermore, in vitro and in silico studies were performed to compare Aβ clearance between mouse and human BBB models. Kinetic studies for Aβ40 disposition in bEnd3 and hCMEC/D3 cells, representative in vitro mouse and human BBB models, respectively, demonstrated 30-fold higher rate of (125)I-Aβ40 uptake and 15-fold higher rate of degradation by bEnd3 compared to hCMEC/D3 cells. Expression studies showed both cells to express different levels of P-glycoprotein and RAGE, while LRP1 levels were comparable. Finally, we established a mechanistic model, which could successfully predict cellular levels of (125)I-Aβ40 and the rate of each process. Established mechanistic model suggested significantly higher rates of Aβ uptake and degradation in bEnd3 cells as rationale for the observed differences in (125)I-Aβ40 disposition between mouse and human BBB models. In conclusion, current study demonstrates the important role of BBB in the clearance of Aβ from the brain. Moreover, it provides insight into the differences between mouse and human BBB with regards to Aβ clearance and offer, for the first time, a mathematical model that describes Aβ clearance across BBB.
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Aβ efflux out of the brain and into peripheral reservoirs such as blood and tissues occurs.
“For example, Aβ efflux out of the brain and into peripheral reservoirs such as the blood and tissues has been shown to occur [22, 23].”
From Alzheimer’s disease-associated protective variant Plcg2-P522R modulates peripheral macrophage function in a sex-dimorphic manner (2024) · cites this paper as [23]
The Introduction states that Aβ40 is cleared from the brain to the blood across the blood–brain barrier, and the Discussion describes transport toward the blood. The passages do not establish that brain-derived Aβ also enters peripheral tissues; a search for peripheral tissue distribution found no supporting passage. (LLM, conf=0.86)
Experimental — accuracy not yet measuredPeripheral monocytes and tissue-resident macrophages participate in Aβ plaque uptake, both around the brain and in peripheral tissue reservoirs.
“This includes evidence that peripheral monocytes and tissue-resident macrophages participate in Aβ plaque uptake, both around the brain and in peripheral tissue reservoirs [22–24].”
From Alzheimer’s disease-associated protective variant Plcg2-P522R modulates peripheral macrophage function in a sex-dimorphic manner (2024) · cites this paper as [23]
The Results (§3.3) report Aβ40 uptake by mouse and human brain endothelial cells, and the Discussion (§4) focuses on endothelial transport across the blood–brain barrier. Searches for monocytes, macrophages, plaque uptake, and peripheral tissue reservoirs found no passage addressing their participation. (LLM, conf=0.76)
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- Authors
- Qosa, H., Abuasal, B. S., Romero, I. A., Weksler, B., Couraud, P.-O., Keller, J. N., & Kaddoumi, A.
- Affiliations
- University of Louisiana at Monroe (US)
- The Open University (GB)
- Inserm (FR)
- Pennington Biomedical Research Center (US)
- Corresponding author
- Kaddoumi, Amal
- ORCID
- Venue
- Neuropharmacology
- Publisher
- Elsevier BV
- Published
- 2014-04
- Volume
- 79
- Pages
- 668-678
- ISSN
- 0028-3908 (ISSN-L)
- PMC
- PMC3965363
- OpenAlex
- W1964623388
- Cited by
- 146
- References
- 47
- Citations by year
- 2026: 8 · 2025: 14 · 2024: 22 · 2023: 8 · 2022: 10 · 2021: 15 · 2020: 7 · 2019: 6 · 2018: 9 · 2017: 14 · 2016: 13 · 2015: 11 · 2014: 9
- FWCI
- 10.45
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Neuropharmacology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Open Research Online (The Open University) (submittedVersion)
- Funders
- National Institute of General Medical Sciences of the National Institutes of Health (P20GM103424)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Keywords
- amyloid-beta clearance, blood-brain barrier, Alzheimer's disease, species differences, human-mouse comparison, Aβ40, bEnd.3 cells, hCMEC/D3 cells, P-glycoprotein, RAGE, LRP1, amyloid beta degradation, mechanistic modeling, kinetic analysis
- MeSH terms
- Receptor for Advanced Glycation End Products, Animals, Blood-Brain Barrier, Brain, Cells, Cultured, Humans, Iodine Radioisotopes, Kinetics, Male, Mice, Inbred C57BL, Models, Neurological, Peptide Fragments, Receptors, Immunologic, Receptors, LDL, Species Specificity, Amyloid beta-Peptides, ATP Binding Cassette Transporter, Subfamily B, Member 1, Tumor Suppressor Proteins, Low Density Lipoprotein Receptor-Related Protein-1, Endothelial Cells, Mice
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