Suppression of glymphatic fluid transport in a mouse model of Alzheimer's disease
Open accessAbstract
Glymphatic transport, defined as cerebrospinal fluid (CSF) peri-arterial inflow into brain, and interstitial fluid (ISF) clearance, is reduced in the aging brain. However, it is unclear whether glymphatic transport affects the distribution of soluble Aβ in Alzheimer's disease (AD). In wild type mice, we show that Aβ40 (fluorescently labeled Aβ40 or unlabeled Aβ40), was distributed from CSF to brain, via the peri-arterial space, and associated with neurons. In contrast, Aβ42 was mostly restricted to the peri-arterial space due mainly to its greater propensity to oligomerize when compared to Aβ40. Interestingly, pretreatment with Aβ40 in the CSF, but not Aβ42, reduced CSF transport into brain. In APP/PS1 mice, a model of AD, with and without extensive amyloid-β deposits, glymphatic transport was reduced, due to the accumulation of toxic Aβ species, such as soluble oligomers. CSF-derived Aβ40 co-localizes with existing endogenous vascular and parenchymal amyloid-β plaques, and thus, may contribute to the progression of both cerebral amyloid angiopathy and parenchymal Aβ accumulation. Importantly, glymphatic failure preceded significant amyloid-β deposits, and thus, may be an early biomarker of AD. By extension, restoring glymphatic inflow and ISF clearance are potential therapeutic targets to slow the onset and progression of AD.
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Inhibition of glymphatic transport leads to significant accumulation of Aβ in APP/PS1 mouse brain.
“Moreover, inhibition of glymphatic transport leads to a significant accumulation of Aβ in APP/PS1 mouse brain [415].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [415]
Infusion of amyloid-β into CSF acutely reduces glymphatic activity in wild-type mice, suggesting a direct toxic effect.
“Infusion of amyloid-β into CSF acutely reduced glymphatic activity in wild-type mice suggesting a direct toxic effect (50, 55).”
From Glymphatic failure as a final common pathway to dementia (2020) · cites this paper as [55]
Glymphatic CSF influx and CSF clearance are reduced in early amyloid deposition in the APP/PS1 Alzheimer disease model compared with littermate controls, and CSF clearance continues to decline as amyloid burden increases.
“glymphatic CSF influx and CSF clearance are each reduced in early stages of amyloid deposition in the APP/PS1 model of Alzheimer disease, compared with littermate controls; CSF clearance continues to decline as the amyloid burden increases (Fig. 1b).”
From Glymphatic failure as a final common pathway to dementia (2020) · cites this paper as [55]
Both the brain glymphatic and meningeal lymphatic systems deteriorate with age and their dysfunction can potentiate AD pathology and dementia.
“both the brain glymphatic and meningeal lymphatic systems deteriorate with age”
From Living on the Edge of the CNS: Meninges Cell Diversity in Health and Disease (2021) · cites this paper as Peng et al., 2016
In the APP/PS1 mouse model of AD, glymphatic dysfunction as measured by CSF clearance rates was impaired, and injection of amyloid-β into the CSF reduced glymphatic activity.
“In the APP/PS1 mouse model of AD, glymphatic dysfunction as measured by CSF clearance rates was impaired”
From Living on the Edge of the CNS: Meninges Cell Diversity in Health and Disease (2021) · cites this paper as Peng et al., 2016
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- Authors
- Peng, W., Achariyar, T. M., Li, B., Liao, Y., Mestre, H., Hitomi, E., Regan, S., Kasper, T., Peng, S., Ding, F., Benveniste, H., Nedergaard, M., & Deane, R.
- Affiliations
- University of Rochester Medicine (US)
- Stony Brook University (US)
- Corresponding author
- Deane, Rashid
- ORCID
- Venue
- Neurobiology of Disease
- Publisher
- Elsevier BV
- Published
- 2016-09
- Volume
- 93
- Pages
- 215-225
- ISSN
- 0969-9961 (ISSN-L)
- PMC
- PMC4980916
- OpenAlex
- W2397614738
- Cited by
- 580
- References
- 76
- Citations by year
- 2026: 59 · 2025: 61 · 2024: 92 · 2023: 69 · 2022: 76 · 2021: 55 · 2020: 52 · 2019: 48 · 2018: 44 · 2017: 20 · 2016: 3
- FWCI
- 21.50
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Neurobiology of Disease (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institutes of Health
- National Institute of Neurological Disorders and Stroke
- National Institute of Aging
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Cerebrospinal fluid and hydrocephalus
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Keywords
- glymphatic system, Alzheimer's disease, cerebrospinal fluid, interstitial fluid clearance, amyloid-beta, Aβ40, amyloid-beta 42, amyloid oligomers, APP/PS1 mice, cerebral amyloid angiopathy, amyloid plaques, early biomarkers, therapeutic target
- MeSH terms
- Alzheimer Disease, Animals, Biological Transport, Brain, Disease Models, Animal, Mice, Inbred C57BL, Neurons, Amyloid beta-Peptides, Disease Progression, Plaque, Amyloid
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