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Fate of Cerebrospinal Fluid‐Borne Amyloid β‐Peptide: Rapid Clearance into Blood and Appreciable Accumulation by Cerebral Arteries
Abstract
In Alzheimer's disease, the neuritic or senile amyloid plaques in hippocampus and association cortex, the diffuse plaques in brain areas such as the cerebellum and sensorimotor cortex, and the amyloid deposits in the walls of pial and parenchymal blood vessels are mainly composed of amyloid beta-peptides. In the present study, either soluble 40-residue amyloid beta-peptide radiolabeled with 125I (I-sAbeta) or [14C]polyethylene glycol ([14C]PEG, a reference material) was briefly infused into one lateral ventricle of normal rats. By 3.5 min, 30% of the I-sAbeta was cleared from ventricular CSF into blood; another 30% was removed over the next 6.5 min. No [14C]PEG was lost from the CSF-brain system during the first 5 min, and only 20% was cleared by 10 min. Much of the I-sAbeta that reached the subarachnoid space was retained by pial arteries and arterioles. Virtually no I-sAbeta was found in brain. The clearance of amyloid beta-peptides from the CSF-brain system, reported herein for normal rats, may be reduced in Alzheimer's disease, thus contributing to amyloid deposition in cerebral tissue and blood vessels.
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In the citing paper
“because CSF A, which has a high concentration relative to plasma A, is normally cleared into blood (Ghersi-Egea et al., 1996).”
From Age-Dependent Changes in Brain, CSF, and Plasma Amyloid β Protein in the Tg2576 Transgenic Mouse Model of Alzheimer's Disease (2001) · cites this paper as Ghersi-Egea et al., 1996
In the citing paper
“The absolute amounts of both tracers in the CSF and plasma were low, however, due to relatively rapid clearance from the CSF in comparison to slow ISF bulk flow (29), and significant systemic body clearance (48), respectively.”
From Clearance of Alzheimer’s amyloid-β1-40 peptide from brain by LDL receptor–related protein-1 at the blood-brain barrier (2000) · cites this paper as [29]
In the citing paper
“Transport of A b out of the CSF was not associated with significant degradation of peptide in the CSF (29).”
From Clearance of Alzheimer’s amyloid-β1-40 peptide from brain by LDL receptor–related protein-1 at the blood-brain barrier (2000) · cites this paper as [29]
In the citing paper
“Lower levels of A b 1-40 than inulin in the CSF may suggest active transport of A b from the CSF to the blood, possibly across the choroid plexus or leptomeningeal vessels, as shown previously (29).”
From Clearance of Alzheimer’s amyloid-β1-40 peptide from brain by LDL receptor–related protein-1 at the blood-brain barrier (2000) · cites this paper as [29]
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“It has been demonstrated that the clearance of A from the brain across the BBB is significantly influenced by its carrier protein (104).”
BackgroundMorley, J. E., & Banks, W. A. (2010) · Journal of Alzheimer's Disease · doi:10.3233/jad-2010-091576 · Cited by 108
Monro, O. (2002) · Neurobiology of Aging · doi:10.1016/s0197-4580(01)00317-7 · Cited by 107
Self-citationQuantification of cerebrospinal fluid transport across the cribriform plate into lymphatics in rats
Nagra, G., Koh, L., Zakharov, A., Armstrong, D., & Johnston, M. G. (2006) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00235.2006 · Cited by 107
“For instance, the half-lives in CSF of soluble amyloid peptide, sucrose, or PEG4000 were 8 min, 60 min, and 60 min, respectively (12, 13).”
BackgroundThe blood-brain barrier: connecting the gut and the brain
Banks, W. A. (2008) · Regulatory Peptides · doi:10.1016/j.regpep.2007.08.027 · Cited by 104
The unsolved relationship of brain aging and late-onset Alzheimer disease
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“Clearance experiments in rats depicted that after infusion of radiolabelled Aβ into the brain 30% of the injected peptides were found in blood and urine withinminutes andwere soon taken up by the liver or kidney [174].”
BackgroundEffect of Different Anti-Aβ Antibodies on Aβ Fibrillogenesis as Assessed by Atomic Force Microscopy
Legleiter, J. A., Czilli, D. L., Gitter, B. D., Demattos, R. B., Holtzman, D. M., & Kowalewski, T. (2003) · Journal of Molecular Biology · doi:10.1016/j.jmb.2003.11.019 · Cited by 105
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Serum amyloid-beta levels are increased in patients with obstructive sleep apnea syndrome
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“We found that consistent with other studies [ 5 ], Aβ40 is rapidly cleared from the brain across the BBB; however, Aβ42 is cleared much less effectively.”
BackgroundMethodResultInfluentialHemin and related porphyrins inhibit β‐amyloid aggregation
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“Studies conducted in animal models showed that the elimination half-life of A between CSF and plasma is about 30 minutes [12, 15, 16].”
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“The a5b1 integrin may play a role in the rapid clearance of Ab that occurs in the normal brain ( Ghersi-Egea et al., 1996 ).”
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“Consistent with the prior work demonstrating that intact [125I]Ab40 was removed from the mouse brain (Shibata et al., 2000), rat CSF (Ghersi-Egea et al., 1996) and/or guinea pig CSF and brain (Monro et al., 2002), a spot chick analysis in one middle-aged and one old monkey indicated that at the end…”
BackgroundResultSelf-citationChoroid plexus and ageing in rats: a morphometric and ultrastructural study
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Nagaraja, T. N., Patel, P., Gorski, M., Gorevic, P. D., Patlak, C. S., & Fenstermacher, J. D. (2005) · Cerebrospinal Fluid Research · doi:10.1186/1743-8454-2-5 · Cited by 74
“The clearance of ~50% of it by 15 min and ~80% by 30 min is far faster than that of sucrose [14] or PEG4000 [13] which had no clearance over the first 5 min and apparent halflives ~60 min for both.”
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“These findings indicate that the kidney may be a potential peripheral organ that participates in the physiological clearance of brain-derived Aβ peptides (Ghersi-Egea et al., 1996; Ghiso et al., 1997; Xiang et al., 2015).”
BackgroundApolipoprotein E influences amyloid-beta clearance from the murine periphery
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“There is accumulating evidence that factors regulating A β catabolism [1], aggregation[2] and clearance [3,4] also play significant roles in the majority of AD cases.”
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Cerebral Amyloid Angiopathy: A Common Cause of Cerebral Hemorrhage
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“In addition to perivascular drainage, A is also cleared actively across the blood-brain barrier to the blood [83-85].”
Metadata
- Authors
- Ghersi‐Egea, J. ‐., Gorevic, P. D., Ghiso, J., Frangione, B., Patlak, C. S., & Fenstermacher, J. D.
- Affiliations
- Stony Brook University (US)
- NYU Langone Health (US)
- Henry Ford Hospital (US)
- Corresponding author
- Fenstermacher, J. D.
- Venue
- Journal of Neurochemistry
- Publisher
- Wiley
- Published
- 1996-08
- Volume
- 67
- Issue
- 2
- Pages
- 880-883
- ISSN
- 0022-3042 (ISSN-L)
- 1471-4159
- OpenAlex
- W2065410730
- Cited by
- 222
- References
- 0
- Citations by year
- 2025: 3 · 2024: 7 · 2023: 2 · 2022: 5 · 2021: 3 · 2020: 3 · 2019: 5 · 2018: 6 · 2017: 8 · 2016: 7 · 2015: 9 · 2014: 8 · 2013: 8 · 2012: 7
- FWCI
- 3.37
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Neurochemistry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Eli Lilly and Company
- National Institutes of Health (5r01ns026004-05, 5r29ag010593-05)
- National Institute on Aging (AG10593, AG05891)
- National Institute of Neurological Disorders and Stroke (NS-26004)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Clinical Neurology › Cerebrospinal fluid and hydrocephalus
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Keywords
- amyloid-beta, cerebrospinal fluid, blood-CSF barrier, cerebral arteries, pial arteries, amyloid deposition, Alzheimer's disease, subarachnoid space
- MeSH terms
- Animals, Cerebral Arteries, Humans, Male, Metabolic Clearance Rate, Peptide Fragments, Amyloid beta-Peptides, Rats, Sprague-Dawley, Rats
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