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(American Journal of Pathology. 1999;155:2115-2125.)
© 1999 American Society for Investigative Pathology

Regular Articles

Agrin Is a Major Heparan Sulfate Proteoglycan Accumulating in Alzheimer’s Disease Brain

Marcel M. Verbeek^*, Irene Otte-Höller^*, Jacob van den Born, Lambert P. W. J. van den Heuvel, Guido David^§, Pieter Wesseling^*¶ and Robert M. W. de Waal^*

From the Departments of Pathology,^*
Nephrology,
Pediatrics,
and Neurology,^¶
University Hospital Nijmegen, Nijmegen, The Netherlands; and the Center for Human Genetics,^§
University of Leuven and Flanders Interuniversity Institute for Biotechnology, Leuven, Belgium

Heparan sulfate proteoglycans (HSPGs) have been suggested to play an important role in the formation and persistence of senile plaques and neurofibrillary tangles in dementia of the Alzheimer’s type (DAT). We performed a comparative immunohistochemical analysis of the expression of the HSPGs agrin, perlecan, glypican-1, and syndecans 1–3 in the lesions of DAT brain neocortex and hippocampus. Using a panel of specific antibodies directed against the protein backbone of the various HSPG species and against the glycosaminoglycan (GAG) side-chains, we demonstrated the following. The basement membrane-associated HSPG, agrin, is widely expressed in senile plaques, neurofibrillary tangles and cerebral blood vessels, whereas the expression of the other basement membrane-associated HSPG, perlecan, is lacking in senile plaques and neurofibrillary tangles and is restricted to the cerebral vasculature. Glypican and three different syndecans, all cell membrane-associated HSPG species, are also expressed in senile plaques and neurofibrillary tangles, albeit at a lower frequency than agrin. Heparan sulfate GAG side chains are also associated with both senile plaques and neurofibrillary tangles. Our results suggest that glycosaminoglycan side chains of the HSPGs agrin, syndecan, and glypican, but not perlecan, may play an important role in the formation of both senile plaques and neurofibrillary tangles. In addition, we speculate that agrin, because it contains nine protease-inhibiting domains, may protect the protein aggregates in senile plaques and neurofibrillary tangles against extracellular proteolytic degradation, leading to the persistence of these deposits.

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