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.