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In vivo assessment of brain interstitial fluid with microdialysis reveals plaque-associated changes in amyloid-beta metabolism and half-life.
J Neurosci. 2003 Oct 01; 23(26):8844-53.JN

Abstract

Soluble amyloid-beta (Abeta) peptide converts to structures with high beta-sheet content in Alzheimer's disease (AD). Soluble Abeta is released by neurons into the brain interstitial fluid (ISF), in which it can convert into toxic aggregates. Because assessment of ISF Abeta levels may provide unique insights into Abeta metabolism and AD, an in vivo microdialysis technique was developed to measure it. Our Abeta 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 Abeta in hippocampus and cortex correlated with levels of APP in those tissues. After the onset of Abeta deposition, significant changes in the ISF Abeta40/Abeta42 ratio developed without changes in Abeta1-x. These changes differed from changes seen in tissue lysates from the same animals. By rapidly inhibiting Abeta production, we found that ISF Abeta half-life was short (approximately 2 hr) in young mice but was twofold longer in mice with Abeta deposits. This increase in half-life, without an increase in steady-state levels, suggests that inhibition of Abeta synthesis reveals a portion of the insoluble Abeta pool that is in dynamic equilibrium with ISF Abeta. This now measurable in vivo pool is a likely target for new diagnostic and therapeutic strategies.

Authors+Show Affiliations

Department of Neurology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

14523085

Citation

Cirrito, John R., et al. "In Vivo Assessment of Brain Interstitial Fluid With Microdialysis Reveals Plaque-associated Changes in Amyloid-beta Metabolism and Half-life." The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, vol. 23, no. 26, 2003, pp. 8844-53.
Cirrito JR, May PC, O'Dell MA, et al. In vivo assessment of brain interstitial fluid with microdialysis reveals plaque-associated changes in amyloid-beta metabolism and half-life. J Neurosci. 2003;23(26):8844-53.
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. (2003). In vivo assessment of brain interstitial fluid with microdialysis reveals plaque-associated changes in amyloid-beta metabolism and half-life. The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, 23(26), 8844-53.
Cirrito JR, et al. In Vivo Assessment of Brain Interstitial Fluid With Microdialysis Reveals Plaque-associated Changes in Amyloid-beta Metabolism and Half-life. J Neurosci. 2003 Oct 1;23(26):8844-53. PubMed PMID: 14523085.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - In vivo assessment of brain interstitial fluid with microdialysis reveals plaque-associated changes in amyloid-beta metabolism and half-life. AU - Cirrito,John R, AU - May,Patrick C, AU - O'Dell,Mark A, AU - Taylor,Jennie W, AU - Parsadanian,Maia, AU - Cramer,Jeffrey W, AU - Audia,James E, AU - Nissen,Jeffrey S, AU - Bales,Kelly R, AU - Paul,Steven M, AU - DeMattos,Ronald B, AU - Holtzman,David M, PY - 2003/10/3/pubmed PY - 2003/11/13/medline PY - 2003/10/3/entrez SP - 8844 EP - 53 JF - The Journal of neuroscience : the official journal of the Society for Neuroscience JO - J. Neurosci. VL - 23 IS - 26 N2 - Soluble amyloid-beta (Abeta) peptide converts to structures with high beta-sheet content in Alzheimer's disease (AD). Soluble Abeta is released by neurons into the brain interstitial fluid (ISF), in which it can convert into toxic aggregates. Because assessment of ISF Abeta levels may provide unique insights into Abeta metabolism and AD, an in vivo microdialysis technique was developed to measure it. Our Abeta 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 Abeta in hippocampus and cortex correlated with levels of APP in those tissues. After the onset of Abeta deposition, significant changes in the ISF Abeta40/Abeta42 ratio developed without changes in Abeta1-x. These changes differed from changes seen in tissue lysates from the same animals. By rapidly inhibiting Abeta production, we found that ISF Abeta half-life was short (approximately 2 hr) in young mice but was twofold longer in mice with Abeta deposits. This increase in half-life, without an increase in steady-state levels, suggests that inhibition of Abeta synthesis reveals a portion of the insoluble Abeta pool that is in dynamic equilibrium with ISF Abeta. This now measurable in vivo pool is a likely target for new diagnostic and therapeutic strategies. SN - 1529-2401 UR - https://www.unboundmedicine.com/medline/citation/14523085/In_vivo_assessment_of_brain_interstitial_fluid_with_microdialysis_reveals_plaque_associated_changes_in_amyloid_beta_metabolism_and_half_life_ L2 - http://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=14523085 DB - PRIME DP - Unbound Medicine ER -