Department of Neurosciences, School of Medicine, Case Western Reserve University, Cleveland, OH, USA.
Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland, OH, USA.
Cell Death Dis. 2022 Nov 10;13(11):952. doi: 10.1038/s41419-022-05378-4.
Alzheimer's disease (AD) is the most common form of dementia. Notably, patients with AD often suffer from severe sarcopenia. However, their direct link and relationship remain poorly understood. Here, we generated a mouse line, TgAPP, by crossing LSL (LoxP-STOP-LoxP)-APP with HSA-Cre mice, which express APP (Swedish mutant APP) selectively in skeletal muscles. Examining phenotypes in TgAPP mice showed not only sarcopenia-like deficit, but also AD-relevant hippocampal inflammation, impairments in adult hippocampal neurogenesis and blood brain barrier (BBB), and depression-like behaviors. Further studies suggest that APP expression in skeletal muscles induces senescence and expressions of senescence-associated secretory phenotypes (SASPs), which include inflammatory cytokines and chemokines; but decreases growth factors, such as PDGF-BB and BDNF. These changes likely contribute to the systemic and hippocampal inflammation, deficits in neurogenesis and BBB, and depression-like behaviors, revealing a link of sarcopenia with AD, and uncovering an axis of muscular APP to brain in AD development.
阿尔茨海默病（AD）是最常见的痴呆症形式。值得注意的是，AD 患者常患有严重的肌肉减少症。然而，它们之间的直接联系和关系仍未得到很好的理解。在这里，我们通过将 LSL（LoxP-STOP-LoxP）-APP 与 HSA-Cre 小鼠杂交，生成了一种 TgAPP 小鼠系，该小鼠系在骨骼肌中选择性表达 APP（瑞典突变 APP）。研究 TgAPP 小鼠的表型不仅显示出类似肌肉减少症的缺陷，还显示出与 AD 相关的海马炎症、成年海马神经发生和血脑屏障（BBB）受损以及抑郁样行为。进一步的研究表明，骨骼肌中 APP 的表达诱导衰老和衰老相关分泌表型（SASPs）的表达，包括炎症细胞因子和趋化因子；但减少生长因子，如 PDGF-BB 和 BDNF。这些变化可能导致全身和海马炎症、神经发生和 BBB 受损以及抑郁样行为，揭示了肌肉减少症与 AD 的联系，并揭示了 AD 发展中肌肉 APP 到大脑的轴。
