Understanding the basic mechanism that control the formation, maintenance and reinnervation of synapses is critical to our understanding of the malfunction of these synapses in disease. Of all the synapses in the body the neuromuscular junction has been most studied due to its relative simplicity and accessibility. Agrin is a heparin sulfate proteoglycan and is an integral member of the synaptic basal lamina. We have shown that agrin is quickly and efficiently removed from synaptic basal lamina during normal synaptic remodelling, and following reinnervation. We have also found that matrix metalloproteinase-3 (MMP-3) removes agrin from synaptic basal lamina, and antibodies to MMP-3 recognize molecules concentrated at the neuromuscular junction. Synaptic activity results in the activation and release of MMP-3 like molecules from stimulated muscle, and subsequent removal of agrin from synaptic basal lamina. Thus, we hypothesize that MMP-3 is responsible for the activity dependent removal of agrin from synaptic basal. Further, we hypothesize that synaptic remodelling is a result of the balance between the removal of agrin from synaptic basal lamina by proteases and the secretion of agrin by the nerve terminal. The neuromuscular junction is a model system for synapses in the brain, and our investigations into the cellular mechanism that controls agrin distribution will have strong implications in our understanding of the mechanisms that lead to Alzheimer's disease. Immunohistochemistry has revealed that agrin and MMP-3 are colocalized to plaques and tangles in Alzheimer's disease. Further, agrin has been shown to enhance the formation of amyloid fibrils, and is hypothesized to trigger plaque formation in the brain. Here we will investigate the basic mechanisms controlling agrin cleavage at the neuromuscular junction, and this information will have direct implications in our understanding of the functioning and malfunctioning of synapses throughout the body.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS033320-06A1
Application #
6287751
Study Section
Special Emphasis Panel (ZRG1-BDCN-2 (01))
Program Officer
Nichols, Paul L
Project Start
1995-06-01
Project End
2004-08-31
Budget Start
2000-09-30
Budget End
2001-08-31
Support Year
6
Fiscal Year
2000
Total Cost
$262,500
Indirect Cost
Name
University of Kansas
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
016060860
City
Kansas City
State
KS
Country
United States
Zip Code
66160