Deposition of amyloid fibrils in the brain is a histopathologic hallmark of Alzheimer disease (AD) and β-amyloid protein (Aβ), the principal component of amyloid fibrils, has been implicated in the neuropathogenesis of AD. In the present study, we first developed an in vitro model of Aβ-induced neurodegeneration using human fetal brain-cell cultures and then tested the hypothesis that cytokines modulate Aβ-induced neurodegeneration. When brain-cell cultures were exposed to Aβ, marked neuronal loss (60% of neurons by microscopic assessment) and functional impairment (i.e., reduction in uptake of [3H]γ-aminobutryric acid) were observed after 6 d of incubation. Aβ-induced neurodegeneration was dose-dependent with maximal effect at 100 μM. Although interleukin (IL)-1, IL-6 and tumor necrosis factor (TNF)-α had a nominal effect, both the β1 and β2 isoforms of transforming growth factor-β dose-dependently protected >50% of neurons against Aβ-induced injury. IL-4 also proved to be neuroprotective. Aβ-induced neurodegeneration was accompanied by microglial cell proliferation and enhanced release of IL-1, IL-6, and TNF-α. These findings are consistent with the emerging concept that AD is an inflammatory disease and may lead to new therapeutic strategies aimed at reducing Aβ-induced neurotoxicity.
- transforming growth factor-β