| Genetic, biochemical, and animal model studies demonstrate that the 38--43 amino acid amyloid-beta peptide (Abeta) plays a central role in the pathogenesis of Alzheimer's disease (AD). Soluble Abeta is released by neurons into the brain interstitial fluid (ISF) where, in the setting of diseases such as AD, it converts into toxic, insoluble aggregates (e.g. plaques). ISF Abeta is likely the main source of Abeta found in plaques. Using a novel in vivo microdialysis technique to assess ISF and a transgenic mouse model of AD (PDAPP), we determined that while the overall levels of ISF Abeta 1-x do not change significantly as PDAPP mice develop plaques, the individual Abeta subspecies change (40/42) and Abeta metabolism is affected. These changes are related to Abeta deposition and not to aging. Utilizing potent gamma-secretase inhibitors in vivo, our findings suggest that Abeta-containing plaques are dynamic structures that can dissociate under appropriate conditions. We also found that the Abeta-binding molecule, apolipoprotein E, plays a direct role in ISF Abeta clearance, whereas clusterin (another Abeta-binding molecule) likely has an effect on Abeta structure, but not clearance. This data furthers our understanding of the crucial pool of ISF Abeta that contributes to AD pathogenesis and has implications in understanding the role of apoE in AD, as well as in AD diagnosis and treatment. |
