title: Accumulation of intracellular amyloid-beta peptide (A beta 1-40) in mucopolysaccharidosis brains.
abstract: To evaluate whether in vivo accumulations of heparan sulfate caused by inborn 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, with mucopolysaccharidosis (MPS). The brains of patients with Hurler's syndrome (MPS I: n = 5) and Sanfilippo's syndrome (MPS III; n = 4) as well as from caprine MPS IIID and murine MPS VII models were evaluated by thioflavine-S staining and by immunohistochemistry using antibodies directed against heparan sulfate proteoglycans, hyperphosphorylated tau, amyloid-beta peptide precursor proteins (APP), and amyloid-beta peptides (A beta [1-40], and A beta [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. Although no neurofibrillary tangles, senile plaques, or tau-positive lesions were detected in any of the MPS brains studied here, antibodies directed against A beta (1-40) intensely and diffusely stained the cytoplasm of cells throughout the brains of the MPS patients and the caprine MPS model. The ELISA assay also demonstrated a significant 3-fold increase in the level of soluble A beta (1-40) in the MPS brains compared with normal control brains. Thus, at least some of the metabolic defects that lead to accumulations of glycosaminoglycans in MPS also are associated with an increase in immunoreactive A beta (1-40) within the cytoplasmic compartment where they could contribute to the dysfunction and death of affected cells in these disorders, but not induce the formation of plaques and tangles. Models of MPS may enable mechanistic studies of the role A beta and glycosaminoglycans play in the amyloidosis that is a neuropathological feature of AD.
authors.affiliation: Center for Neurodegenerative Disease Research and Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia 19104-4283, USA.
authors.forename: S D
authors.initials: SD
authors.lastname: Ginsberg
authors.forename: J E
authors.initials: JE
authors.lastname: Galvin
authors.forename: V M
authors.initials: VM
authors.lastname: Lee
authors.forename: L B
authors.initials: LB
authors.lastname: Rorke
authors.forename: D W
authors.initials: DW
authors.lastname: Dickson
authors.forename: J H
authors.initials: JH
authors.lastname: Wolfe
authors.forename: M Z
authors.initials: MZ
authors.lastname: Jones
authors.forename: J Q
authors.initials: JQ
authors.lastname: Trojanowski
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D000911:Antibodies, Monoclonal; D001921:Brain / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006025:Glycosaminoglycans / Q000378:metabolism; D006041:Goats; D006497:Heparan Sulfate / Q000378:metabolism; D006801:Humans; D007223:Infant; D008297:Male; D051379:Mice; D008875:Middle Aged; D009083:Mucopolysaccharidoses / Q000378:metabolism*; D008059:Mucopolysaccharidosis I / Q000378:metabolism; D009084:Mucopolysaccharidosis III / Q000378:metabolism; D016538:Mucopolysaccharidosis VII / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D000911:Antibodies, Monoclonal; D006025:Glycosaminoglycans; D006497:Heparan Sulfate; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40)