Selective loss of cerebral keratan sulfate in Alzheimer's disease

Proteoglycans, especially heparan sulfate-substituted species, are known to be associated with the deposition of amyloid in Alzheimer's disease. We previously found that heparan sulfate from afflicted brains, and from control subjects, differed minimally in quantity and structure (Lindahl, B., Eriksson, L., and Lindahl, U.(1995) Biochem. J. 306, 177-184). In the present study, a glycosaminoglycan fraction, shown to contain heparan sulfate and keratan sulfate, was radiolabeled by partial N-deacetylation (hydrazinolysis) followed by re-N-acetylation using [3H]acetic anhydride. Quantitation of the 3H-labeled polysaccharides, based on digestion with heparitinase I from Flavobacterium heparinum and keratanase from Pseudomonas sp., revealed that the amounts of keratan sulfate in Alzheimer cerebral cortex are reduced to less than half of control values. Moreover, a monoclonal antibody against a highly sulfated keratan sulfate epitope bound to the majority of the neurons in normal cortex but not in the diseased tissue. The lack of highly sulfated keratan sulfate structures may reflect a specific functional defect of the cells.