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The Journal of Neuroscience, October 1, 2003, 23(26):8844-8853

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Cellular/Molecular
In Vivo Assessment of Brain Interstitial Fluid with Microdialysis Reveals Plaque-Associated Changes in Amyloid- Metabolism and Half-Life

John R. Cirrito,¹ Patrick C. May,⁴ Mark A. O'Dell,¹ Jennie W. Taylor,¹ Maia Parsadanian,¹ Jeffrey W. Cramer,⁵ James E. Audia,⁶ Jeffrey S. Nissen,⁶ Kelly R. Bales,⁴ Steven M. Paul,^4,7 Ronald B. DeMattos,⁴ and David M. Holtzman^1,2,3

Departments of ¹Neurology and ²Molecular Biology and Pharmacology and ³Center for the Study of Nervous System Injury, Washington University School of Medicine, St. Louis, Missouri 63110, ⁴Neuroscience Discovery Research and ⁵Drug Disposition-Lead Optimization, ⁶Discovery Chemistry Research, Eli Lilly and Company, Lilly Research Laboratories, Indianapolis, Indiana 46285, and ⁷Departments of Pharmacology, Toxicology, and Psychiatry, Indiana University School of Medicine, Indianapolis, Indiana 46285

Soluble amyloid- (A) peptide converts to structures with high -sheet content in Alzheimer's disease (AD). Soluble A is released by neurons into the brain interstitial fluid (ISF), in which it can convert into toxic aggregates. Because assessment of ISF A levels may provide unique insights into A metabolism and AD, an in vivo microdialysis technique was developed to measure it. Our A 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 A in hippocampus and cortex correlated with levels of APP in those tissues. After the onset of A deposition, significant changes in the ISF A₄₀/A₄₂ ratio developed without changes in A_1-x. These changes differed from changes seen in tissue lysates from the same animals. By rapidly inhibiting A production, we found that ISF A half-life was short (2 hr) in young mice but was twofold longer in mice with A deposits. This increase in half-life, without an increase in steady-state levels, suggests that inhibition of A synthesis reveals a portion of the insoluble A pool that is in dynamic equilibrium with ISF A. This now measurable in vivo pool is a likely target for new diagnostic and therapeutic strategies.

Key words: Alzheimer; amyloid; interstitial fluid; microdialysis; half-life; gamma-secretase

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Received June 11, 2003; revised August 4, 2003; accepted August 4, 2003.

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