Department of Pharmacology Physiology & Neuroscience New Jersey Medical School, Brain Health Institute, Jacqueline Krieger Klein Center in Alzheimer's Disease and Neurodegeneration Research, Rutgers, The State University of New Jersey, Newark, United States.
Elife. 2020 Feb 5;9:e52612. doi: 10.7554/eLife.52612.
Cleavage of APP by BACE1/β-secretase initiates the amyloidogenic cascade leading to Amyloid-β (Aβ) production. α-Secretase initiates the non-amyloidogenic pathway preventing Aβ production. Several mutations cause familial Alzheimer's disease (AD), while the Icelandic 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 () or the pathogenic Swedish mutation (), also located near the BACE1-cleavage site. α-Cleavage is favored over β-processing in rats. Consequently, non-amyloidogenic and amyloidogenic APP metabolites are increased and decreased, respectively. The reverse APP processing shift occurs in rats. These opposite effects on APP β/α-processing suggest that protection from and pathogenesis of dementia depend upon combinatorial and opposite alterations in APP metabolism rather than simply on Aβ levels. The Icelandic mutation also protects from aging-dependent cognitive decline, suggesting that similar mechanisms underlie physiological cognitive aging.
APP 通过 BACE1/β-分泌酶的裂解启动导致淀粉样蛋白-β (Aβ) 产生的淀粉样蛋白形成级联反应。α-分泌酶启动非淀粉样蛋白形成途径，防止 Aβ 的产生。几种突变导致家族性阿尔茨海默病 (AD)，而冰岛突变位于 BACE1 切割位点附近，可预防散发性痴呆，这强调了 APP 在痴呆发病机制中的作用。为了研究 APP 的保护/致病机制，我们生成了携带保护性 () 或致病性瑞典突变 () 的敲入大鼠，该突变也位于 BACE1 切割位点附近。在 大鼠中，α-裂解优先于 β-处理。因此，非淀粉样蛋白形成和淀粉样蛋白形成的 APP 代谢物分别增加和减少。在 大鼠中则发生相反的 APP 加工转变。APP β/α-加工的这些相反作用表明，痴呆的保护和发病机制取决于 APP 代谢的组合和相反改变，而不仅仅取决于 Aβ 水平。冰岛突变也可防止与年龄相关的认知能力下降，这表明类似的机制是生理认知衰老的基础。
