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