Effects of transforming growth factor-beta (isoforms 1-3) on amyloid-beta deposition, inflammation, and cell targeting in organotypic hippocampal slice cultures.
The transforming growth factor-beta (TGF-beta) family consists of three isoforms and is part of a larger family of cytokines regulating differentiation, development, and tissue repair. Previous work from our laboratory has shown that TGF-beta1 can increase amyloid-beta protein (Abeta) immunoreactive (Abetair) plaque-like deposits in rat brain. The aim of the current study was to evaluate all three isoforms of TGF-beta for their ability to affect the deposition and neurotoxicity of Abeta in an organotypic, hippocampal slice culture model of Abeta deposition. Slice cultures were treated with Abeta either with or without one of the TGF-beta isoforms. All three isoforms can increase Abeta accumulation (over Abeta treatment alone) within the slice culture, as determined by ELISA. However, there are striking differences in the pattern of Abetair among the three isoforms of TGF-beta. Isoforms 1 and 3 produced a cellular pattern of Abeta staining that colocalizes with GS lectin staining (microglia). TGF-beta2 produces dramatic Abeta staining of pyramidal neurons in layers CA1-CA2. In addition to cellular Abeta staining, plaque-like deposits are increased by all of the TGF-betas. Although no gross toxicity was observed, morphological neurodegenerative changes were seen in the CA1 region when the slices were treated with Abeta plus TGF-beta2. Our results demonstrate important functional differences among the TGF-beta isoforms in their ability to alter the cellular distribution and degradation of Abeta. These changes may be relevant to the pathology of Alzheimer's disease (AD).
Harris-White
M E
ME
Department of Medicine, University of California Los Angeles and Veterans Affairs Medical Center Sepulveda, Sepulveda, California 91343, USA.
Chu
T
T
Balverde
Z
Z
Sigel
J J
JJ
Flanders
K C
KC
Frautschy
S A
SA
D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D017077:Culture Media, Conditioned / Q000737:chemistry; D004797:Enzyme-Linked Immunosorbent Assay; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D007249:Inflammation / Q000378:metabolism; D051379:Mice; D008813:Mice, Inbred ICR; D009410:Nerve Degeneration / Q000473:pathology; D020033:Protein Isoforms / Q000494:pharmacology; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D016229:Amyloid beta-Peptides; D000906:Antibodies; D017077:Culture Media, Conditioned; D020033:Protein Isoforms; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha