| First Author | Hong S | Year | 2011 |
| Journal | J Neurosci | Volume | 31 |
| Issue | 44 | Pages | 15861-9 |
| PubMed ID | 22049429 | Mgi Jnum | J:177845 |
| Mgi Id | MGI:5296396 | Doi | 10.1523/JNEUROSCI.3272-11.2011 |
| Citation | Hong S, et al. (2011) Dynamic Analysis of Amyloid beta-Protein in Behaving Mice Reveals Opposing Changes in ISF versus Parenchymal Abeta during Age-Related Plaque Formation. J Neurosci 31(44):15861-9 |
| abstractText | Growing evidence supports the hypothesis that soluble, diffusible forms of the amyloid beta-peptide (Abeta) are pathogenically important in Alzheimer's disease (AD) and thus have both diagnostic and therapeutic salience. To learn more about the dynamics of soluble Abeta economy in vivo, we used microdialysis to sample the brain interstitial fluid (ISF), which contains the most soluble Abeta species in brain at steady state, in >40 wake, behaving APP transgenic mice before and during the process of Abeta plaque formation (age 3-28 months). Diffusible forms of Abeta, especially Abeta(42), declined significantly in ISF as mice underwent progressive parenchymal deposition of Abeta. Moreover, radiolabeled Abeta administered at physiological concentrations into ISF revealed a striking difference in the fate of soluble Abeta 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 Abeta from the ISF. Likewise, acute gamma-secretase inhibition in plaque-free mice showed a marked decline of Abeta(38), Abeta(40), and Abeta(42), whereas in plaque-rich mice, Abeta(42) declined significantly less. These results suggest that most of the Abeta(42) that populates the ISF in plaque-rich mice is derived not from new Abeta biosynthesis but rather from the large reservoir of less soluble Abeta(42) in brain parenchyma. Together, these and other findings herein illuminate the in vivo dynamics of soluble Abeta during the development of AD-type neuropathology and after gamma-secretase inhibition and help explain the apparent paradox that CSF Abeta(42) levels fall as humans develop AD. |
