While total cholesterol levels in brain are apparently not increased in MPSIII, in situ labelling using filipin histochemistry reveals the presence of unesterified cholesterol in individual brain cells. This accumulation occurs as storage-like granules in cell bodies of neurons and glia and has been reported in a wide spectrum of lysosomal diseases, including MPSIIIA, as well as MPSI, MPSII, MPSVI, Niemann-Pick C disease, GM1/GM2 gangliosidosis and Wolman’s disease (Walkley, 2004). Again, all of these diseases share commonality in inflammatory responses, although the precise mechanisms may vary. Other abnormal proteins in MPSRecent studies have demonstrated that neurons in certain brain areas of MPSIIIA and MPSIIIB mice, primarily dentate gyrus and medial entorhinal cortex involved in learning and memory have increased levels of protein markers associated with AD and other tauopathies. Deposition of lysozyme, hyperphosphorylated tau, phosphorylated tau kinase, GSK3B, and amyloid-? and amyloid precursor protein (APP) are all evident in the brains of MPSIII mice (Beard et al.
, 2017; Ohmi et al., 2009; Ohmi et al., 2011). All of these markers are also increased in the brains of HGSNAT-deficient mice although their levels are somewhat lower than those in the MPSIIIA and MPSIIIB mice of similar age (Beard et al., 2017; Ohmi et al.
, 2011). Similar findings are demonstrated in post-mortem brains from MPSIII patients; antibodies directed against amyloid-?(1-40) intensely and diffusely stained the cytoplasm of cells throughout the brains, with a significant 3-fold increase in the level of soluble amyloid-?(1-40) (Ginsberg et al., 1999).
