Dynamic Analysis of Amyloid β-Protein in Behaving Mice Reveals Opposing Changes in ISF versus Parenchymal Aβ during Age-Related Plaque Formation

Growing evidence supports the hypothesis that soluble, diffusible forms of the amyloid beta-peptide (A beta) are pathogenically important in Alzheimer's disease (AD) and thus have both diagnostic and therapeutic salience. To learn more about the dynamics of soluble A beta economy in vivo, we used microdialysis to sample the brain interstitial fluid (ISF), which contains the most soluble A beta species in brain at steady state, in >40 wake, behaving APP transgenic mice before and during the process of A beta plaque formation (age 3-28 months). Diffusible forms of A beta, especially A beta(42), declined significantly in ISF as mice underwent progressive parenchymal deposition of A beta. Moreover, radiolabeled A beta administered at physiological concentrations into ISF revealed a striking difference in the fate of soluble A beta 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 A beta from the ISF. Likewise, acute gamma-secretase inhibition in plaque-free mice showed a marked decline of A beta(38), A beta(40), and A beta(42), whereas in plaque-rich mice, A beta(42) declined significantly less. These results suggest that most of the A beta(42) that populates the ISF in plaque-rich mice is derived not from new A beta biosynthesis but rather from the large reservoir of less soluble A beta(42) in brain parenchyma. Together, these and other findings herein illuminate the in vivo dynamics of soluble A beta during the development of AD-type neuropathology and after gamma-secretase inhibition and help explain the apparent paradox that CSF A beta(42) levels fall as humans develop AD.