Opposite changes in APP processing and human aβ levels in rats carrying either a protective or a pathogenic APP mutation

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Abstract

Cleavage of APP by BACE1/b-secretase initiates the amyloidogenic cascade leading to Amyloid-b (Ab) production. a-Secretase initiates the non-amyloidogenic pathway preventing Ab production. Several APP mutations cause familial Alzheimer's disease (AD), while the Icelandic APP mutation near the BACE1-cleavage site protects from sporadic dementia, emphasizing APP's role in dementia pathogenesis. To study APP protective/pathogenic mechanisms, we generated knock-in rats carrying either the protective (App^p) or the pathogenic Swedish mutation (App^s), also located near the BACE1-cleavage site. a-Cleavage is favored over b-processing in App^p rats. Consequently, non-amyloidogenic and amyloidogenic APP metabolites are increased and decreased, respectively. The reverse APP processing shift occurs in App^s rats. These opposite effects on APP b/a-processing suggest that protection from and pathogenesis of dementia depend upon combinatorial and opposite alterations in APP metabolism rather than simply on Ab levels. The Icelandic mutation also protects from aging-dependent cognitive decline, suggesting that similar mechanisms underlie physiological cognitive aging.

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All data generated and analyzed are included. Source files have been provided for all Figures

Article and author information

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Marc D Tambini

Department of Pharmacology, Physiology and Neuroscience, Rutgers, The State University of New Jersey, Newark, United States

Competing interests
The authors declare that no competing interests exist.
Kelly A Norris

Department of Pharmacology, Physiology and Neuroscience, Rutgers, The State University of New Jersey, Newark, United States

Competing interests
The authors declare that no competing interests exist.
Luciano D'Adamio

Department of Pharmacology, Physiology and Neuroscience, Rutgers, The State University of New Jersey, Newark, United States

For correspondence
luciano.dadamio@rutgers.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-2204-9441

Funding

National Institute on Aging (R01AG063407)

Luciano D'Adamio

National Institute on Aging (RF1AG064821)

Luciano D'Adamio

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: Rats were handled according to the Ethical Guidelines for Treatment of Laboratory Animals of the NIH. The procedures were described and approved by the Institutional Animal Care and Use Committee (IACUC) at Rutgers University.(protocol number 201702513).

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.