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 (Appp) or the pathogenic Swedish mutation (Apps), also located near the BACE1-cleavage site. a-Cleavage is favored over b-processing in Appp rats. Consequently, non-amyloidogenic and amyloidogenic APP metabolites are increased and decreased, respectively. The reverse APP processing shift occurs in Apps 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.
- Luciano D'Adamio
- Luciano D'Adamio
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
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).
- Andrew B West, Duke University, United States
© 2020, Tambini et al.
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