1995 — 1999 |
Gottschall, Paul E |
R29Activity Code Description: Undocumented code - click on the grant title for more information. |
Proteases, Aging, and Neurodegenerative Diseases @ University of South Florida
Evidence suggests that abnormal, yet fundamental interactions among inflammatory mediators, matrix proteins, proteases and protease inhibitors may result in (or interact with) the overproduction of fibril-forming beta-amyloid (Abeta) peptides. This process may initiate the neurotoxic and/or neurotrophic responses characteristic of neuritic plaques in Alzheimer's disease (AD). The functional relationship among these processes is ill-defined. The possibility that the extracellular matrix (ECM) degrading enzymes, the matrix metalloproteinases (MMPs), participate in the neurotrophic and/or neurotoxic responses induced by Abeta is supported by the following: 1) MMPs are essential for neuronal plasticity during early development and they induce neurite growth in vitro; 2) MMP-2 (gelatinase A) may exhibit alpha-secretase activity; 3) an MMP, MMP-3 or stromelysin-1, induced by Abeta only in mixed hippocampal cultures, and not in astrocyte or microglia cultures, has the capacity to degrade a broad spectrum of ECM proteins including heparan sulfate proteoglycan (HSPG); and 4) MMPs are overexpressed in AD hippocampal tissue and cerebrospinal fluid. The proposed experiments will characterize a possible function for the MMPs in Abeta-induced (or kainic acid) neurotoxicity in vitro and identify mechanisms that regulate induced MMP expression and activity. MMP activity and gene expression in tissue from various brain regions will be characterized after intraventricular injection of Abeta or kainic acid. Additionally, it will be determined whether induced MMP activity is altered in the brain of aged animals. Preliminary data indicate that Abeta peptides induce the production of MMP-9 (gelatinase B) in cultured microglia and stimulate the secretion of MMP-9, MMP-2 and MMP-3 in mixed hippocampal cultures. Abeta peptides also induce the secretion of the alpha/2-macroglobulin. The fibril-forming Abeta peptides in combination witH HSPGs and apolipoprotein E could alter subtle, morphological characteristics of neurons, whereas changes in cell shape induce MMP expression. Results from these experiments may define a possible functional relationship between the secretion of MMPs and the well-known neurotoxic and/or neurotrophic action of Abeta.
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0.948 |
2006 — 2010 |
Gottschall, Paul E |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Proteoglycans, Synaptic Plasticity in Aging and Disease @ University of South Florida
[unreadable] DESCRIPTION (provided by applicant): 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. [unreadable] [unreadable]
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0.972 |