TRANSFORMING GROWTH-FACTOR-BETA PROTECTS HUMAN NEURONS AGAINST BETA-AMYLOID-INDUCED INJURY

Deposition of amyloid fibrils in the brain is a histopathologic hallma rk of Alzheimer disease (AD) and beta-amyloid protein (A beta), the pr incipal component of amyloid fibrils, has been implicated in the neuro pathogenesis of AD. In the present study, we first developed an in vit ro model of A beta-induced neurodegeneration using human fetal brain-c ell cultures and then tested the hypothesis that cytokines modulate A beta-induced neurodegeneration. When brain-cell cultures were exposed to A beta, marked neuronal loss (60% of neurons by microscopic assessm ent) and functional impairment (i.e., reduction in uptake of [H-3]gamm a-aminobutryric acid) were observed after 6 d of incubation. A beta-in duced neurodegeneration was dose-dependent with maximal effect at 100 mu M. Although interleukin (IL)-1, IL-6 and tumor necrosis factor (TNF )-alpha had a nominal effect, both the beta 1 and beta 2 isoforms of t ransforming growth factor-beta dose-dependently protected >50% of neur ons against A beta-induced injury. IL-4 also proved to be neuroprotect ive. A beta-induced neurodegeneration was accompanied by microglial ce ll proliferation and enhanced release of IL-1, IL-6, and TNF-alpha. Th ese findings are consistent with the emerging concept that AD is an in flammatory disease and may lead to new therapeutic strategies aimed at reducing A beta-induced neurotoxicity.