Aβ solubility and deposition during AD progression and in APP x PS-1 knock-in mice

Amnestic mild cognitive impairment (MCI) appears to be a very early stage of Alzheimer's disease (AD). The amyloid-P peptide (AP) is believed to be a possible substrate for AD, but little is currently known about AP alterations in MCI and how these changes compare to later stages of disease. In the present study AP was differentially extracted from the brains of age-matched control, MCI, and AD cases and compared with plaque counts. For comparison, APPxPS-1 knock-in mice were processed in parallel. We observed that A beta(42) was significantly elevated in MCI subjects, even though there was no significant alteration in the total amount of A beta. Relative AP solubility within the different extractable pools was identical between AD and MCI subjects, with both significantly altered relative to controls. Temporal analysis of A beta levels and solubility in a knock-in mouse model of AP pathogenesis recapitulated many of the salient features observed in AD. Characterization of the SDS fraction showed some similarities between aged knock-in mice and AD subjects. These data suggest that distinctchanges in A beta occur throughout the progression of A beta, and that elevations in A beta(42) occur at an early, clinically defined stage. (c) 2007 Elsevier Inc. All rights reserved.