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Abeta solubility and deposition during AD progression and in APPxPS-1 knock-in mice
M Paul Murphy1, Tina L Beckett, Qunxing Ding
1Department of Molecular and Cellular Biochemistry, Sanders-Brown Center on Aging, University of Kentucky, Lexington, Kentucky 40536-0230, USA. mpmurp3@email.uky.edu
Abstract:
Amnestic mild cognitive impairment (MCI) appears to be a very early stage of Alzheimer's disease (AD). The amyloid-beta peptide (Abeta) is believed to be a possible substrate for AD, but little is currently known about Abeta alterations in MCI and how these changes compare to later stages of disease. In the present study Abeta 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 Abeta42 was significantly elevated in MCI subjects, even though there was no significant alteration in the total amount of Abeta. Relative Abeta solubility within the different extractable pools was identical between AD and MCI subjects, with both significantly altered relative to controls. Temporal analysis of Abeta levels and solubility in a knock-in mouse model of Abeta 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 Abeta occur throughout the progression of AD, and that elevations in Abeta42 occur at an early, clinically defined stage.
Insights
Alzheimer's disease (AD) research shows amyloid-beta 42 (Abeta42) elevations in mild cognitive impairment (MCI), an early AD stage. These changes in Abeta42 levels and solubility occur early, preceding significant total Abeta alterations.
Area of Science:
- Neuroscience
- Biochemistry
- Pathology
Background:
- Amnestic mild cognitive impairment (MCI) is considered an early stage of Alzheimer's disease (AD).
- Amyloid-beta peptide (Abeta) is implicated in AD pathogenesis, but its specific alterations in MCI remain unclear.
- Understanding Abeta changes in MCI is crucial for early diagnosis and intervention.
Purpose of the Study:
- To investigate Abeta alterations, including levels and solubility, in the brains of individuals with MCI compared to AD and control subjects.
- To compare these changes with those observed in a mouse model of Abeta pathogenesis.
Main Methods:
- Differential extraction of Abeta from human brain samples (control, MCI, AD).
- Quantification of Abeta levels and assessment of solubility across different fractions.
- Parallel processing of APPxPS-1 knock-in mice to model Abeta pathogenesis.
- Comparison of human data with findings from the mouse model.
Main Results:
- Abeta42 was significantly elevated in MCI subjects, despite no significant change in total Abeta.
- Relative Abeta solubility profiles were similar between MCI and AD subjects, both differing from controls.
- Temporal analysis in knock-in mice mirrored key features of Abeta changes seen in AD progression.
- The SDS fraction showed similarities between aged mice and AD subjects.
Conclusions:
- Distinct changes in Abeta occur throughout Alzheimer's disease progression.
- Elevations in Abeta42 are an early event, detectable at the MCI stage.
- These findings highlight the potential of Abeta42 as an early biomarker for AD.
