In Vivo Assessment of Brain Interstitial Fluid with Microdialysis Reveals Plaque-Associated Changes in Amyloid-β Metabolism and Half-Life
Open accessAbstract
Soluble amyloid-β (Aβ) peptide converts to structures with high β-sheet content in Alzheimer's disease (AD). Soluble Aβ is released by neurons into the brain interstitial fluid (ISF), in which it can convert into toxic aggregates. Because assessment of ISF Aβ levels may provide unique insights into Aβ metabolism and AD, an in vivo microdialysis technique was developed to measure it. Our Aβ microdialysis technique was validated ex vivo with human CSF and then in vivo in awake, freely moving mice. Using human amyloid precursor protein (APP) transgenic mice, we found that, before the onset of AD-like pathology, ISF Aβ in hippocampus and cortex correlated with levels of APP in those tissues. After the onset of Aβ deposition, significant changes in the ISF Aβ 40 /Aβ 42 ratio developed without changes in Aβ 1-x . These changes differed from changes seen in tissue lysates from the same animals. By rapidly inhibiting Aβ production, we found that ISF Aβ half-life was short (∼2 hr) in young mice but was twofold longer in mice with Aβ deposits. This increase in half-life, without an increase in steady-state levels, suggests that inhibition of Aβ synthesis reveals a portion of the insoluble Aβ pool that is in dynamic equilibrium with ISF Aβ. This now measurable in vivo pool is a likely target for new diagnostic and therapeutic strategies.
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The concentration of soluble Aβ in the ISF throughout life is closely associated with the amount of Aβ that ultimately deposits in the extracellular space of the brain.
“The concentration of soluble Aβ in the ISF throughout life has been shown to be closely associated with the amount of Aβ that ultimately deposits in the extracellular space of the brain (29-31).”
From Human ApoE isoforms differentially regulate brain amyloid-β peptide clearance (2011) · cites this paper as [29]
The ‘Relationships between ISF Aβ, CSF Aβ, and plaque load’ section reports a trend toward correlation between hippocampal ISF Aβ and plaque load in 12- to 15-month-old PDAPP mice; Figure 5 gives p = 0.1582. This does not establish a close association throughout life or show that ISF concentration predicts the amount ultimately deposited. Our copy provides no page number for these passages. (LLM, conf=0.88)
Experimental — accuracy not yet measuredSoluble ISF Aβ exchangeable across a 38kDa dialysis membrane (eAβ) is tightly correlated with the levels of total soluble Aβ present in extracellular pools of the brain.
“Soluble ISF Aβ exchangeable across a 38kDa dialysis membrane (eAβ) has previously been shown to be tightly correlated with the levels of total soluble Aβ present in extracellular pools of the brain (Cirrito et al., 2003).”
From Overexpression of Low-Density Lipoprotein Receptor in the Brain Markedly Inhibits Amyloid Deposition and Increases Extracellular Aβ Clearance (2009) · cites this paper as Cirrito et al., 2003
The “Characterization of Aβ in human CSF” section reports a high correlation between exchangeable Aβ and total soluble Aβ in human CSF, using a 35 kDa membrane. It does not establish that correlation for brain ISF or extracellular pools generally. The paper also describes ISF as distinct from CSF and soluble brain-tissue lysates. (LLM, conf=0.89)
Experimental — accuracy not yet measuredThe half-life of Aβ clearance in previous studies ranged from 30 min to 2 h.
“The half-life of Aβ clearance in these studies ranged from 30 min to 2 h.”
From Measurement of apolipoprotein E and amyloid β clearance rates in the mouse brain using bolus stable isotope labeling (2012) · cites this paper as [49]
The Results section ('Half-life of Aβ in the brain interstitial fluid'; page unavailable) reports an ISF Aβ half-life of 1.97 hours in young mice, supporting the 2-hour figure. It does not report a 30-minute half-life; it also reports 3.78 hours in aged mice, so the stated range does not describe this paper's findings. (LLM, conf=0.87)
Experimental — accuracy not yet measuredSoluble ISF Aβ closely reflects extracellular pools of Aβ.
“Because soluble ISF Aβ has been shown to closely reflect extracellular pools of Aβ (29-31)”
From Human ApoE isoforms differentially regulate brain amyloid-β peptide clearance (2011) · cites this paper as [29]
Previous studies have measured Aβ clearance from the brain either using 35S]methionine labeling or by measuring the disappearance of Aβ following the pharmacological inhibition of Aβ production.
“Previous studies have measured Aβ clearance from the brain either using 35 S]methionine labeling [48], or by measuring the disappearance of Aβ following the pharmacological inhibition of Aβ production [49-51].”
From Measurement of apolipoprotein E and amyloid β clearance rates in the mouse brain using bolus stable isotope labeling (2012) · cites this paper as [49]
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Self-citationTampellini, D., Rahman, N., Gallo, E. F., Huang, Z., Dumont, M., Capetillo-Zarate, E., Ma, T., Zheng, R., Lu, B., Nanus, D. M., et al. (2009) · The Journal of Neuroscience · doi:10.1523/jneurosci.2292-09.2009 · Cited by 127 · see citing works
Insights into the mechanisms of action of anti‐Aβ antibodies in Alzheimer's disease mouse models
Levites, Y., Smithson, L. A., Price, R. W., Dakin, R. S., Yuan, B., Sierks, M. R., Kim, J., McGowan, E., Kim Reed, D., Rosenberry, T. L., et al. (2006) · The FASEB Journal · doi:10.1096/fj.06-6463fje · Cited by 113 · see citing works
Hong, S., Quintero-Monzon, O., Ostaszewski, B. L., Podlisny, D. R., Cavanaugh, W. T., Yang, T., Holtzman, D. M., Cirrito, J. R., & Selkoe, D. J. (2011) · The Journal of Neuroscience · doi:10.1523/jneurosci.3272-11.2011 · Cited by 111 · see citing works
Self-citationAnti-Amyloid Therapies for Alzheimer’s Disease and the Amyloid Cascade Hypothesis
Fedele, E. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241914499 · Cited by 102 · see citing works
Anti-tau antibody administration increases plasma tau in transgenic mice and patients with tauopathy
Yanamandra, K., Patel, T. K., Jiang, H., Schindler, S., Ulrich, J. D., Boxer, A. L., Miller, B. L., Kerwin, D. R., Gallardo, G., Stewart, F., et al. (2017) · Science Translational Medicine · doi:10.1126/scitranslmed.aal2029 · Cited by 100 · see citing works
Self-citationThe relationship between amyloid-beta and brain capillary endothelial cells in Alzheimer’s disease
Su, Q., Guo, J.-H., Zhang, Y.-L., Wang, J., & Zhang, Z.-N. (2022) · Neural Regeneration Research · doi:10.4103/1673-5374.335829 · Cited by 91 · see citing works
Aβ oligomers inhibit synapse remodelling necessary for memory consolidation
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Imaging of cerebrovascular pathology in animal models of Alzheimer's disease
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“To test this hypothesis, we estimated the half-life of A in ISF using reverse microdialysis with the -secretase inhibitor compound E to acutely block A production within the local environment of the microdialysis probe while following its decay over time (19, 39).”
MethodResultTrem2 deficiency differentially affects phenotype and transcriptome of human APOE3 and APOE4 mice
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In vivo imaging reveals sigmoidal growth kinetic of β-amyloid plaques
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Role of Family History for Alzheimer Biomarker Abnormalities in the Adult Children Study
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Self-citationGenetic and pharmacological evidence of intraneuronal Aβ accumulation in APP transgenic mice
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Semagacestat for Treatment of Alzheimer's Disease
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- Authors
- Cirrito, J. R., May, P. C., O'Dell, M. A., Taylor, J. W., Parsadanian, M., Cramer, J. W., Audia, J. E., Nissen, J. S., Bales, K. R., Paul, S. M., DeMattos, R. B., & Holtzman, D. M.
- Affiliations
- Eli Lilly (United States) (US)
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2003-10-01
- Volume
- 23
- Issue
- 26
- Pages
- 8844-8853
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- OpenAlex
- W4321429567
- Cited by
- 394
- References
- 10
- Citations by year
- 2026: 8 · 2025: 8 · 2024: 7 · 2023: 28 · 2022: 19 · 2021: 10 · 2020: 23 · 2019: 13 · 2018: 15 · 2017: 23 · 2016: 15 · 2015: 28 · 2014: 23 · 2013: 22 · 2012: 28
- FWCI
- 5.76
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neuroscience (publishedVersion)
- Funders
- MetLife Foundation
- Eli Lilly and Company
- National Institutes of Health (RR‐00036, AG13956, AG11355)
- National Institute on Aging (AG11355, AG20222, R01AG020222, R01AG013956, R37AG013956, AG13956, P01AG011355)
- National Center for Research Resources (M01-RR00036, M01RR000036)
- 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
- amyloid-beta, brain interstitial fluid, Alzheimer's disease, amyloid plaques, amyloid-beta metabolism, amyloid precursor protein transgenic mice, hippocampus, cerebrospinal fluid, microdialysis
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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