Zinc finger protein 335 mediates lipopolysaccharide-induced neurodegeneration and memory loss as a transcriptional factor in microglia.

Zinc finger protein 335 (Zfp335) is a transcription factor that regulates mammalian neurogenesis and neuronal differentiation. It is a causative factor for severe microcephaly, small somatic size, and neonatal death. Here, we evaluated the effects of Zfp335 in the adult mouse brain after lipopolysaccharide (LPS) challenge. We used wild-type (WT) and Zfp335 knock-down (Zfp335+/- ) mice with LPS administered in the intracerebral ventricle in vivo and cultured microglia treated with LPS in vitro. The impact of Zfp335 was evaluated by RT-PCR, RNA-sequencing, western blotting, immunocytochemistry, ELISA, and the memory behavior tests. Knockdown of Zfp335 expression ameliorated microglia activation significantly, including reduced mRNA and protein expression of Iba1, reduced numbers of microglia, reduced cell diameter, and increased branch length, in the brains of 2-month-old mice after LPS treatment. Zfp335 was expressed in microglia and neurons, but increased in microglia, not neurons, in the brain of mice after LPS administration. LPS-induced microglia-mediated neurodegeneration was dependent upon microglial Zfp335 controlled by nuclear factor-kappa B. Microglial Zfp335 affected neuronal activity through transcriptional regulation of lymphocyte antigen-6M (Ly6M). Our data suggest that Zfp335 is a key transcription factor that exacerbates microglia-mediated neurodegeneration through upregulation of Ly6M expression. Inhibition of microglial Zfp335 may be a new strategy for preventing brain disease induced by microglia activation.

Research progress of cathepsin B in brain aging and Alzheimer's diseases.

Cathepsin B (CatB), a cysteine protease derived from lysosomes, was initially thought to non-selectively degrade proteins from phagocytosis and autophagy in lysosomes. However, CatB has been demonstrated to selectively degrade and specifically activate target proteins, thereby regulating the process of physiological and pathological responses. The expression, enzymatic activity, and cellular localization of CatB are significantly altered in brain aging and age-related neurodegenerative diseases. Therefore, the pathological function of CatB has attracted much attention in neuroscience research. In this review, we systematically summarize the molecular functions of CatB in brain aging and Alzheimer's disease and discuss the current problems in neuropathological studies of CatB, which lay a foundation for a comprehensive understanding of the pathogenesis of aging and Alzheimer's disease.