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

Abstract

Amnestic mild cognitive impairment (MCI) appears to be a very early stage of Alzheimer’s disease (AD). The amyloid-β peptide (Aβ) is believed to be a possible substrate for AD, but little is currently known about Aβ alterations in MCI and how these changes compare to later stages of disease. In the present study Aβ was differentially extracted from the brains of age-matched control, MCI, and AD cases and compared with plaque counts. For comparison, APP×PS-1 knock-in mice were processed in parallel. We observed that Aβ42 was significantly elevated in MCI subjects, even though there was no significant alteration in the total amount of Aβ. Relative Aβ solubility within the different extractable pools was identical between AD and MCI subjects, with both significantly altered relative to controls. Temporal analysis of Aβ levels and solubility in a knock-in mouse model of Aβ 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 distinct changes in Aβ occur throughout the progression of AD, and that elevations in Aβ42 occur at an early, clinically defined stage.

Keywords

• Alzheimer’s disease
• Amyloid-β peptide
• Amyloid precursor protein
• Mild cognitive impairment
• Neuritic plaque
• Animal model