Transforming growth factor-beta protects human neurons against beta-amyloid-induced injury.
Deposition of amyloid fibrils in the brain is a histopathologic hallmark of Alzheimer disease (AD) and beta-amyloid protein (A beta), 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 A beta-induced neurodegeneration using human fetal brain-cell 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 assessment) and functional impairment (i.e., reduction in uptake of [3H]gamma-aminobutyric acid) were observed after 6 d of incubation. A beta-induced neurodegeneration was dose-dependent with maximal effect at 100 microM. 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 transforming growth factor-beta dose-dependently protected > 50% of neurons against A beta-induced injury. IL-4 also proved to be neuro-protective. A beta-induced neurodegeneration was accompanied by microglial cell proliferation and enhanced release of IL-1, IL-6, and TNF-alpha. These findings are consistent with the emerging concept that AD is an inflammatory disease and may lead to new therapeutic strategies aimed at reducing A beta-induced neurotoxicity.
Chao
C C
CC
Neuroimmunobiology and Host Defense Laboratory, Minneapolis Medical Research Foundation, MN 55404.
Hu
S
S
Kravitz
F H
FH
Tsang
M
M
Anderson
W R
WR
Peterson
P K
PK
D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000633:toxicity*; D001921:Brain / Q000166:cytology; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000502:physiology; D006801:Humans; D017628:Microglia / Q000187:drug effects; D009410:Nerve Degeneration / Q000187:drug effects; D009474:Neurons / Q000187:drug effects*; D011994:Recombinant Proteins / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D016229:Amyloid beta-Peptides; D016207:Cytokines; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta