Muscular Swedish mutant APP-to-Brain axis in the development of Alzheimer’s disease

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(swe)(HSA), by crossing LSL (LoxP-STOP-LoxP)-APP(swe) with HSA-Cre mice, which express APP(swe) (Swedish mutant APP) selectively in skeletal muscles. Examining phenotypes in TgAPP(swe)(HSA) 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(swe) 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(swe) to brain in AD development.