Heparan Sulfate Accumulation in the Beta-Amyloid Protein Containing Lesions of Down’s Syndrome Occurs Prior to the Appearance of Fibrillar Amyloid

Abstract

In the present study, a monoclonal antibody (HK-249) that recognizes a glucosamine sulfate alpha 1→4 glucuronic acid-containing determinant in heparan sulfate (HS) chains of a basement membrane derived heparan sulfate proteoglycan was used to identify and localize HS in Downs syndrome (DS) brain, and to determine the sequence of events preceding the formation and accumulation of: fibrillar amyloid in DS. Analysis of DS patients at different ages revealed that HS accumulated within neurons of the hippocampus and amygdala, as early as 1 day after birth. Young age-matched controls did not demonstrate similar positive HS immunoreactivity in neurons whereas positive immunostaining for HS was observed in other regions thought to normally contain HS. The earliest deposition of betaamyloid protein (BAP) was first observed as “amorphous” or “diffuse” cortical deposits in DS brain in patients aged 18 and 24, prior to the accumulation of fibrillar amyloid (observed in DS patients 35 years and older). These cortical deposits also contained positive HS immunoreactivity implying that HS accumulation in conjunction with the BAP is an early event preceding the first appearance of fibrillar amyloid.