Dynamic Analysis of Amyloid β-Protein in Behaving Mice Reveals Opposing Changes in ISF versus Parenchymal Aβ during Age-Related Plaque Formation
Open accessAbstract
Growing evidence supports the hypothesis that soluble, diffusible forms of the amyloid β-peptide (Aβ) are pathogenically important in Alzheimer's disease (AD) and thus have both diagnostic and therapeutic salience. To learn more about the dynamics of soluble Aβ economy in vivo, we used microdialysis to sample the brain interstitial fluid (ISF), which contains the most soluble Aβ species in brain at steady state, in >40 wake, behaving APP transgenic mice before and during the process of Aβ plaque formation (age 3–28 months). Diffusible forms of Aβ, especially Aβ 42, declined significantly in ISF as mice underwent progressive parenchymal deposition of Aβ. Moreover, radiolabeled Aβ administered at physiological concentrations into ISF revealed a striking difference in the fate of soluble Aβ in plaque-rich (vs plaque-free) mice: it clears more rapidly from the ISF and becomes more associated with the TBS-extractable pool, suggesting that cerebral amyloid deposits can rapidly sequester soluble Aβ from the ISF. Likewise, acute γ-secretase inhibition in plaque-free mice showed a marked decline of Aβ 38, Aβ 40, and Aβ 42, whereas in plaque-rich mice, Aβ 42 declined significantly less. These results suggest that most of the Aβ 42 that populates the ISF in plaque-rich mice is derived not from new Aβ biosynthesis but rather from the large reservoir of less soluble Aβ 42 in brain parenchyma. Together, these and other findings herein illuminate the in vivo dynamics of soluble Aβ during the development of AD-type neuropathology and after γ-secretase inhibition and help explain the apparent paradox that CSF Aβ 42 levels fall as humans develop AD.
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J20 mice show significant loss of synapses in hippocampal CA1 stratum radiatum at 3-4 months old, an age preceding plaque deposition.
“Quantification of colocalized pre- and postsynaptic puncta (synaptophysin and PSD95 (Fig. 1A); synaptotagmin and homer (figs. S1A-D)) revealed a significant loss of synapses in J20 hippocampus at 3-4 months old (mo), an age that precedes plaque deposition (11, 12).”
From Complement and microglia mediate early synapse loss in Alzheimer mouse models (2016) · cites this paper as [12]
Punctate Aβ was deposited in J20 hippocampus at 1 mo, long before Aβ plaques deposit.
“Punctate Aβ was found deposited in J20 hippocampus at 1 mo (Fig. S4), long before Aβ plaques deposit (11, 12)”
From Complement and microglia mediate early synapse loss in Alzheimer mouse models (2016) · cites this paper as [12]
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- Authors
- 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.
- Affiliations
- Brigham and Women's Hospital (US)
- Washington University in St. Louis (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2011-11-02
- Volume
- 31
- Issue
- 44
- Pages
- 15861-15869
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC3227224
- OpenAlex
- W2124217561
- Cited by
- 111
- References
- 40
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 6 · 2023: 4 · 2022: 3 · 2021: 2 · 2020: 5 · 2019: 2 · 2018: 5 · 2017: 4 · 2016: 11 · 2015: 9 · 2014: 20 · 2013: 22 · 2012: 14
- FWCI
- 12.43
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Digital Commons@Becker (Washington University School of Medicine) (submittedVersion)
- Funders
- Harvard NeuroDiscovery Center
- Yale University
- Georgia Clinical and Translational Science Alliance (UL1 RR024139)
- National Institutes of Health (AG13956)
- National Institute on Aging (AG027443, R01AG013956, AG017574-08S1, R01AG027443, R01AG017574, K01AG029524, R01AG012749, R37AG013956, AG13956, R01AG006173)
- National Center for Research Resources (RR024139, UL1RR024139)
- Yale Center for Clinical Investigation, Yale School of Medicine (UL1RR024139)
- 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, Alzheimer's disease, interstitial fluid, brain parenchyma, gamma-secretase inhibition, APP transgenic mice, microdialysis
- MeSH terms
- Age Factors, Aging, Alzheimer Disease, Analysis of Variance, Animals, Brain, Disease Models, Animal, Enzyme-Linked Immunosorbent Assay, Glycerol, Iodine Isotopes, Mice, Transgenic, Wakefulness, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Microdialysis, Nonlinear Dynamics, Pyruvic Acid, Lactase, Extracellular Fluid, Mice, Plaque, Amyloid
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