Correlation between sarcopenia and changes in oligodendrocyte lineage cells in the brains of Alzheimer's disease model mice

Alzheimer's disease (AD) is a neurodegenerative disorder primarily characterized by cognitive dysfunction. The discovery and identification of non-cognitive symptoms in the preclinical stage hold promise for early diagnosis and intervention. Previous studies have shown that diagnosed AD patients commonly exhibit alterations in sarcopenia-related indicators, which might represent early symptoms of progression from mild cognitive impairment (MCI) to AD. This study used 3-month-old APP/PS1 transgenic (AD) mice and C57BL/6J wild-type (WT) mice. Hindlimbs were immobilized with plaster casts for 2 weeks. After immobilization, body, brain, and muscle weights were measured. Behavioral tests were conducted. Immunofluorescence staining was used to assess muscle morphology and analyze oligodendrocyte precursor cells (OPCs) lineage-related indicators. Hindlimb immobilization induced sarcopenia in both AD and WT mice, manifested as decreased body, brain, gastrocnemius (Gas), and soleus (Sol) muscle weights. Immobilized mice showed decreased motor ability and impaired exploration behavior. Long-term spatial learning and memory were also affected. Muscle histological analysis revealed that AD mice exhibited baseline muscle fiber type switching. After immobilization, AD mice showed increased proportions of MyHC IIa fast-twitch fibers in the Sol and MyHC IIb fast-twitch fibers in the tibialis anterior (TA). At the central nervous system level, immobilization inhibited the OPCs proliferation and significantly increased activation of microglia and astrocytes of immobilized mice. Hindlimb immobilization-induced sarcopenia correlated with slow-to-fast fiber transformation, reduced OPCs proliferation, and enhanced neuroinflammation. This study highlights the importance of sarcopenia in the progression of AD-related white matter pathology. • The study combined APP/PS1 transgenic AD mice with a hindlimb immobilization-induced sarcopenia model to mimic the muscle atrophy seen in bedridden or inactive AD patients. • It is the first to systematically investigate the effect of sarcopenia induced by hindlimb immobilization on the proliferation and differentiation of OPCs in the brain. • In the AD model, sarcopenia was accompanied by a significant shift from slow-twitch to fast-twitch muscle fiber types, which may establish functional connectivity along the “muscle–brain axis” through the regulation of myokine secretion. • Changes in sarcopenia and related muscle indicators may appear earlier than typical cognitive symptoms, holding potential as biomarkers for early AD risk assessment.