Heparan sulfate proteoglycans (HSPGs) are ubiquitously present within the perivascular basement membrane, and have been shown to be altered in patients with
Alzheimer's Disease (AD). Although the
HSPG agrin clearly orchestrates the differentiation of the neuromuscular junction, its role in the brain remains unclear. Growing evidence suggests that
agrin may be an important vascular basement membrane (VBM)-associated
HSPG. In previous studies, we demonstrated that
agrin is present throughout the brain microvasculature, as well as in neuronal cell bodies. AD brains exhibited fragmentation of VBM-associated
agrin.
Agrin immunoreactivity was also seen within
senile plaques and neurofibrillary tangles. These changes were accompanied by the appearance of an additional pool of insoluble
agrin. In the present study, we provide further evidence for microvascular damage in AD, by examining the distribution of
agrin and
laminin within the VBM, and by measuring the
agrin concentration within hippocampus and prefrontal cortex. Furthermore, we assessed blood-brain-barrier (BBB) leakage by examining the perivascular distribution of
prothrombin immunoreactivity. Soluble
agrin levels were increased approximately 30% in Braak stage III-VI AD patients relative to age-matched controls. Furthermore,
agrin and
laminin exhibited identical patterns of VBM fragmentation in AD and colocalized with
beta-amyloid in
senile plaques. Microvascular changes were associated with the appearance of perivascular
prothrombin immunoreactivity. Our data suggest that
agrin is an important VBM-associated
HSPG in the brain and that
agrin levels are altered in association with microvascular damage in AD.