title: Dynamic analysis of amyloid β-protein in behaving mice reveals opposing changes in ISF versus parenchymal Aβ during age-related plaque formation.
abstract: 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.
authors: Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
authors: Soyon
authors: S
authors: Hong
authors: Omar
authors: O
authors: Quintero-Monzon
authors: Beth L
authors: BL
authors: Ostaszewski
authors: Daniel R
authors: DR
authors: Podlisny
authors: William T
authors: WT
authors: Cavanaugh
authors: Ting
authors: T
authors: Yang
authors: David M
authors: DM
authors: Holtzman
authors: John R
authors: JR
authors: Cirrito
authors: Dennis J
authors: DJ
authors: Selkoe
mesh_terms: D000367:Age Factors; D000375:Aging / Q000473:pathology*; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000473:pathology*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D045604:Extracellular Fluid / Q000378:metabolism*; D005990:Glycerol / Q000378:metabolism; D007456:Iodine Isotopes / Q000493:pharmacokinetics; D043322:Lactase / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D017551:Microdialysis / Q000379:methods; D017711:Nonlinear Dynamics; D058225:Plaque, Amyloid / Q000503:physiopathology*; D019289:Pyruvic Acid / Q000378:metabolism; D014851:Wakefulness
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D007456:Iodine Isotopes; D019289:Pyruvic Acid; D043322:Lactase; D005990:Glycerol