Accumulation of intracellular amyloid-beta peptide (A beta 1-40) in mucopolysaccharidosis brains

To evaluate whether in vivo accumulations of heparan sulfate caused by inbo rn errors in the metabolism of glycosaminoglycans lead to the formation of neurofibrillary tangles and/or senile plaques, as seen in Alzheimer disease (AD), we studied postmortem brains from 9 patients, ages 1 to 42 years, wi th mucopolysaccharidosis (MPS). The brains of patients with Hurler's syndro me (MPS I; n = 5) and Sanfilippo's syndrome (MPS III; n = 4) as well as fro m caprine MPS IIID and murine MPS VII models were evaluated by thioflavine- S staining and by immunohistochemistry using antibodies directed against he paran sulfate proteoglycans, hyperphosphorylated tau, amyloid-beta peptide precursor proteins (APP), and amyloid-beta peptides (A beta [1-40], and A b eta [1-42]). A two-site sandwich enzyme-linked immunosorbent assay (ELISA) was also utilized to compare levels of total soluble and insoluble A beta ( 1-40) and A beta (1-42) obtained from temporal cortex of MPS patients. Alth ough no neurofibrillary tangles, senile plaques, or tau-positive lesions we re detected in any of the MPS brains studied here, antibodies directed agai nst A beta (1-40) intensely and diffusely stained the cytoplasm of cells th roughout the brains of the MPS patients and the caprine MPS model. The ELIS A assay also demonstrated a significant 3-fold increase in the level of sol uble A beta (1-40) in the MPS brains compared with normal control brains. T hus, at least some of the metabolic defects that lead to accumulations of g lycosaminoglycans in MPS also are associated with an increase in immunoreac tive A beta (1-40) within the cytoplasmic compartment where they could cont ribute to the dysfunction and death of affected cells in these disorders, b ut not induce the formation of plaques and tangles. Models of MPS may enabl e mechanistic studies of the role A beta and glycosaminoglycans play in the amyloidosis that is a neuropathological feature of AD.