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 α-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 Gsk3β. 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 was found in MEC of
MPS IIIB mice outside of lysosomes. We propose that it is the extralysosomal
glypican that would be harmful to neurons, because its
heparan sulfate branches could potentiate the formation of Ptau and
beta amyloid aggregates, which would be toxic as well as difficult to degrade.