INCREASED CENTRAL-NERVOUS-SYSTEM PRODUCTION OF EXTRACELLULAR-MATRIX COMPONENTS AND DEVELOPMENT OF HYDROCEPHALUS IN TRANSGENIC MICE OVEREXPRESSING TRANSFORMING GROWTH-FACTOR-BETA-1

A number of important neurological diseases, including HIV-1 encephali tis, Alzheimer's disease, and brain trauma, are associated with increa sed cerebral expression of the multifunctional cytokine transforming g rowth factor-beta 1 (TGF-beta 1). To determine whether overexpression of TGF-beta 1 within the central nervous system (CNS) can contribute t o the development of neuropathological alterations, a bioactive form o f TGF-beta 1 was expressed in astrocytes, of transgenic mice, Transgen ic mice with high levels of cerebral TGF-beta 1 expression developed a severe communicating hydrocephalus, seizures, motor incoordination, a nd early runting. While unmanipulated heterozygous transgenic mice fro m a low expressor line showed no such alterations, increasing TGF-beta 1 expression in this line by injury-induced astroglial activation or generation of homozygous offspring did result in the abnormal phenotyp e. Notably, astroglial overexpression of TGF-beta 1 consistently induc ed a strong upmodulation of the extracellular matrix proteins laminin and fibronectin in the CNS, particularly in the vicinity of TGF-beta 1 -expressing perivascular astrocytes, but was not associated with obvio us CNS infiltration by hematogenous cells, While low levels of extrace llular matrix protein expression may assist in CNS wound repair and re generation excessive extracellular matrix deposition could result in t he development of hydrocephalus. As an effective inducer of extracellu lar matrix components, TFG-beta 1 may also contribute to the developme nt of other neuropathological alterations, eg, the formation of amyloi d plaques in Alzheimer's disease.