defects in the medial entorhinal cortex and dentate gyrus in the mouse model of sanfilippo syndrome type b缺陷在内侧内嗅皮层和齿状回礼宾部主管综合征小鼠模型的b型.pdf

Defects in the Medial Entorhinal Cortex and Dentate Gyrus in the Mouse Model of Sanfilippo Syndrome Type B Kazuhiro Ohmi, Hui-Zhi Zhao, Elizabeth F. Neufeld* Department of Biological Chemistry, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America Abstract Sanfilippo syndrome type B (MPS IIIB) is characterized by profound mental retardation in childhood, dementia and death in late adolescence; it is caused by deficiency of a-N-acetylglucosaminidase and resulting lysosomal storage of heparan sulfate. A mouse model, generated by homologous recombination of the Naglu gene, was used to study pathological changes in the brain. We found earlier that neurons in the medial entorhinal cortex (MEC) and the dentate gyrus showed a number of secondary defects, including the presence of hyperphosphorylated tau (Ptau) detected with antibodies raised against Ptau in Alzheimer disease brain. By further use of immunohistochemistry, we now show staining in neurons of the same area for beta amyloid, extending the resemblance to Alzheimer disease. Ptau inclusions in the dentate gyrus of MPS IIIB mice were reduced in number when the mice were administered LiCl, a specific inhibitor of Gsk3b. Additional proteins found elevated in MEC include proteins involved in autophagy and the heparan sulfate proteoglycans, glypicans 1 and 5, the latter closely related to the primary defect. The level of secondary accumulations was associated with elevation of glypican, as seen by comparing brains of mice at different ages or with different mucopolysaccharide storage diseases. The MEC of an MPS IIIA mouse had the same intense immunostaining for glypican 1 and other markers as MPS IIIB, while MEC of MPS I and MPS II mice had weak staining, and MEC of an MPS VI mouse had no staining at all for the same proteins. A considerable amount of glypican