Heparan sulphate
proteoglycan (
HSPG) and
amyloid P component are the only macromolecules consistently associated with all varieties of
amyloid, irrespective of the type of
amyloid protein, suggesting that
HSPG may play a pathogenetic role in
amyloid formation through a common mechanism. In the case of
Alzheimer's disease (AD),
HSPG, such as
perlecan, co-accumulates with
amyloid-beta protein (Abeta), a main constituent of
amyloid plaques, and paired helical filaments (PHFs). Additionally, in vitro,
HSPG accelerates both Abeta fibril and PHF formation and protects Abeta from degradation. Therefore, this study first established lines of P19 mouse embryonic
carcinoma cells stably carrying an expression vector encoding the complete
perlecan core
protein (approximately 400 kD). In the cell lysates, overexpressed
perlecan was identified as an approximately 400 kD
protein without
glycosaminoglycan side-chains, while in the media, secreted
perlecan was mostly glycosylated, suggesting that the secretion and glycosylation of
perlecan are coupled. Next, transgenic mice were produced using the same expression vector. Marked
perlecan overexpression occurred in the cytoplasm of multiple tissues including the brain, heart, kidney, and pancreas, without a discernible increase of
perlecan in extracellular matrices. The transgenic mice up to 18 months of age did not develop
amyloid or AD-like pathology in the brain or elsewhere, based on histochemical and immunohistochemical analyses. Thus, overproduction of
perlecan core
protein is insufficient to lead to
amyloidosis and AD-like pathology.