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

• DOI: 10.7554/elife.52612
• Publication Date: 2020-02-05T13:01:15Z
• Authors: Marc D Tambini; Kelly A Norris; Luciano D'Adamio
• Keywords: Pathogenesis; Cleavage (geology)

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