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The Evolution of Aβ Peptide Burden in the APP23 Transgenic Mice: Implications for Aβ Deposition in Alzheimer Disease

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Abstract

Background

High levels of Aβ in the cerebral cortex distinguish demented Alzheimer’s disease (AD) from nondemented elderly individuals, suggesting that decreased amyloid-beta (Aβ) peptide clearance from the brain is a key precipitating factor in AD.

Materials and Methods

The levels of Aβ in brain and plasma as well as apolipoprotein E (ApoE) in brain were investigated by enzyme-linked immunosorbent assay (ELISA) and Western blotting at various times during the life span of the APP23 transgenic (Tg) and control mice. Histochemistry and immunocytochemistry were used to assess the morphologic characteristics of the brain parenchymal and cerebrovascular amyloid deposits and the intracellular amyloid precursor protein (APP) deposits in the APP23 Tg mice.

Results

No significant differences were found in the plasma levels of Aβ between the APP23 Tg and control mice from 2–20 months of age. In contrast, soluble Aβ levels in the brain were continually elevated, increasing 4-fold at 2 months and 33-fold in the APP23 Tg mice at 20 months of age when compared to the control mice. Soluble Aβ42 was about 60% higher than Aβ40. In the APP23 Tg mice, insoluble Aβ40 remained at basal levels in the brain until 9 months and then rose to 680 µg/g cortex by 20 months. Insoluble Aβ40 was negligible in non-Tg mice at all ages. Insoluble Aβ42 in APP23 Tg mice rose to 60 µg/g cortex at 20 months, representing 24 times the control Aβ42 levels. Elevated levels of ApoE in the brain were observed in the APP23 Tg mice at 2 months of age, becoming substantially higher by 20 months. ApoE colocalized with Aβ in the plaques. Beta-amyloid precursor protein (βAPP) deposits were detected within the neuronal cytoplasm from 4 months of age onward. Amyloid angiopathy in the APP23 Tg mice increased markedly with age, being by far more severe than in the Tg2576 mice.

Conclusions

We suggest that the APP23 Tg mouse may develop an earlier blockage in Aβ clearance than the Tg2576 mice, resulting in a more severe accumulation of Aβ in the perivascular drainage pathways and in the brain. Both Tg mice reflect decreased Aβ elimination and as models for the amyloid cascade they are useful to study AD pathophysiology and therapy.

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Acknowledgments

This study was partially supported by The State of Arizona Alzheimer’s Disease Research Center and by the National Institutes of Health (AG-17490).

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Authors and Affiliations

  1. The Longtine Center for Molecular Biology and Genetics, Sun Health Research Institute, 10515 West Santa Fe Drive, Sun City, Arizona, 85351, USA

    Yu-Min Kuo, Walter M. Kalback, Dean C. Luehrs, Tatiana A. Vishnivetskaya &  Alex E. Roher

  2. The Civin Laboratory of Neuropathology, Sun Health Research Institute, Sun City, Arizona, USA

    Thomas G. Beach, Lucia I. Sue, Sarah Scott & Kathryn J. Layne

  3. Department of Microbiology, Midwestern University, Glendale, Arizona, USA

    Tyler A. Kokjohn

  4. Novartis Pharma, Inc., Basel, Switzerland

    Dorothee Abramowski, Christine Sturchler-Pierrat & Matthias Staufenbiel

  5. Department of Pathology, University of Southampton School of Medicine, Southampton General Hospital, Southampton, UK

    Roy O. Weller

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  1. Yu-Min Kuo
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Correspondence to Alex E. Roher.

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Kuo, YM., Beach, T.G., Sue, L.I. et al. The Evolution of Aβ Peptide Burden in the APP23 Transgenic Mice: Implications for Aβ Deposition in Alzheimer Disease. Mol Med 7, 609–618 (2001). https://doi.org/10.1007/BF03401867

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