Agrin in Alzheimer's disease: Altered solubility and abnormal distributionwithin microvasculature and brain parenchyma

Agrin is a heparan sulfate proteoglycan that is widely expressed in neurons and microvascular basal lamina in the rodent and avian central nervous sys tem. Agrin induces the differentiation of nerve-muscle synapses, but its fu nction in either normal or diseased brains is not known. Alzheimer's diseas e (AD) is characterized by loss of synapses, changes in microvascular archi tecture, and formation of neurofibrillary tangles and senile plaques. Here we have asked whether AD causes changes in the distribution and biochemical properties of agrin. Immunostaining of normal, aged human central nervous system revealed that agrin is expressed in neurons in multiple brain areas. Robust agrin immunoreactivity was observed uniformly in the microvascular basal lamina. In AD brains, agrin is highly concentrated in both diffuse an d neuritic plaques as well as neurofibrillary tangles; neuronal expression of agrin also was observed. Furthermore, patients with AD had microvascular alterations characterized by thinning and fragmentation of the basal lamin a. Detergent extraction and Western blotting showed that virtually all the agrin in normal brain is soluble in 1% SDS. In contrast, a large fraction o f the agrin in AD brains is insoluble under these conditions, suggesting th at it is tightly associated with P-amyloid. Together, these data indicate t hat the agrin abnormalities observed in AD are closely linked to P-amyloid deposition. These observations suggest that altered agrin expression in the microvasculature and the brain parenchyma contribute to the pathogenesis o f AD.