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.