SUMMARY Impaired degradation of amyloid beta (Aβ) peptides could lead to Aβ accumulation, an early trigger of Alzheimer’s disease (AD). Regulation of Aβ-degrading enzymes remains largely unknown. Cystatin C (CysC, CST3) is an endogenous inhibitor of cysteine proteases, including cathepsin B (CatB), a recently discovered Aβ-degrading enzyme. The CST3 polymorphism is also associated with an increased risk of late-onset sporadic AD. Here we identified CysC as the key inhibitory mechanism of CatB-induced Aβ degradation in vivo. Genetic ablation of CST3 in hAPP-J20 mice significantly lowered soluble Aβ levels, the relative abundance of Aβ1–42, and plaque load. CysC removal also attenuated Aβ-associated cognitive deficits, behavioral abnormalities, and restored synaptic plasticity in the hippocampus. Importantly, the beneficial effects of CysC reduction were abolished on a CatB null background, providing direct evidence that CysC regulates soluble Aβ and Aβ-associated neuronal deficits through inhibiting CatB-induced Aβ degradation.

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We explored the mechanism of early stage osteonecrotic femoral head collapse by analyzing and comparing different regions in human osteonecrotic femoral head samples. Eight osteonecrotic femoral heads (ARCO II-III) were obtained from patients undergoing total hip arthroplasty. Bone structure was observed and evaluated by micro-computed tomography (CT) scans and pathology. Osteoblast and osteoclast activities were detected by tartrate-resistant acid phosphatase, alkaline phosphatase, and immunofluorescent staining. Some trabeculae had microfractures in the subchondral bone and necrotic region, which had lower bone mineral density, as well as trabecular thickness and number, but greater osteoclast activity. A sclerotic band had already appeared in certain samples which had greater trabecular thickness and number, bone mineral density, and osteoblast activity. The appearance of the femoral head did not change significantly in the early stage of osteonecrosis of the femoral head. However, osteoblast and osteoclast activities had already changed in different regions of the osteonecrotic femoral head, which may lead to eventual collapse of the femoral head. Therefore, osteonecrosis of the femoral head must be treated during the early stage. In addition, osteoblast activity should be promoted and osteoclast activity inhibited as early as possible to prevent collapse of an osteonecrotic femoral head.