The aggregating chondroitin sulfate proteoglycan (CSPG, in general, lectican), brevican, surrounds, but is not on or over, synaptic contacts, and is highly expressed in the adult central nervous system. Brevican, in complex with other matrix molecules, may stabilize synaptic contacts. Disruption of the CSPG complex by proteolytic cleavage of one of the components, would allow the matrix to become more fluid, permit mobility and possibly the formation of new synaptic contacts. The finding that cortical areas abundant in CSPGs (as measured by a generalized CSPG antibody) are protected from changes in Alzheimer's disease (AD) pathology lends credence to the converse hypothesis that those regions with a more fluid matrix and lower levels of CSs, i.e., shorter core protein CSPG that has less CS, core protein without CS, or cleaved CSPG, may be more susceptible to AD pathology. The hypothesis that diminished proteolytic remodeling of perisynaptic brevican may be a component in the loss of synaptic plasticity in AD and models of disease, forms the basis of this proposal. Preliminary data demonstrate that a fragment derived from ADAMTS-cleavage of brevican is markedly reduced in AD hippocampus, compared to neurologically-diseased control and these levels are correlated with synaptic density and inversely correlated with astrocyte activation. Interestingly, intact brevican core protein is more abundant in hippocampus from old rats compared to young rats. Lectican-cleaving ADAMTSs (a disintegrin and metalloproteinase with thrombospondin repeats) are expressed early on in an excitotoxic model of brain injury and that they actively cleave brevican. These newly generated brevican fragments are located in areas with a marked loss of synapses where plastic responses are well known to occur, such as the molecular layer of the dentate gyrus. The proposed experiments will characterize ADAMTS expression and brevican cleavage in models of neurodegeneration, examine the effects of altered proteolytic activity on synaptic remodeling, and determine whether the normal course of brevican cleavage is altered after entorhinal cortex lesion in young and old rats and mouse models of AD. Should synaptic remodeling be altered, due to diminished proteolytic cleavage of brevican, stimulation of proteolysis may be of therapeutic value. ? ?
