Physical inactivity is one of risk factors for Alzheimer’s disease (AD). Performing physical exercise is difficult at old age, and thus, decline in physical movement may be a cause of age-associated lowering of the brain function. This study aimed to elucidate the onset of the skeletal muscle atrophy-induced acceleration of AD and its molecular mechanism.
Presymptomatic AD model (5XFAD) mice were used. The bilateral hindlimbs were immobilized by cast-attachment for 14 days. Wet weight of hindlimbs muscles were significantly lower in cast-attached 5XFAD mice than those in non-cast mice. At the same time, object recognition memory in the cast-attached 5XFAD mice was impaired. The hindlimb muscles were organ cultured. And the conditioned media (CM) was separated by 2D-PAGE and analyzed by MALDI-TOF MS. The most increased spot in the cast-attached muscle CM was hemopexin. Hemopexin levels in the skeletal muscle, plasma, and hippocampus were increased in cast-attached 5XFAD mice. Continuous i.c.v. infusion of hemopexin for 2 weeks induced memory deficits in young 5XFAD mice. Gene microarray analysis of the hippocampus was performed to investigate the molecules involved in memory deficit. Lipocalin-2 (Lcn2) mRNA, neuroinflammation-associated factor, was increased in the hippocampus in hemopexin-infused 5XFAD mice compared to in control mice.
These findings provide new evidence indicating that skeletal muscle atrophy has an unbeneficial impact on the occurrence of memory impairment in 5XFAD mice, which is mediated by skeletal muscle atrophy-driven hemopexin.