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.

R29AG012160

1995-05-05

2001-04-30