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 iso forms and is part of a larger family of cytokines regulating differentiatio n, development, and tissue repair. Previous work from our laboratory has sh own that TGF-beta 1 can increase amyloid-beta protein (A beta) immunoreacti ve (A beta ir) plaque-like deposits in rat brain. The aim of the current st udy was to evaluate all three isoforms of TGF-beta for their ability to aff ect the deposition and neurotoxicity of A beta in an organotypic, hippocamp al slice culture model of A beta deposition. Slice cultures were treated wi th A beta either with or without one of the TGF-beta isoforms. All three is oforms can increase A beta accumulation (over A beta treatment alone) withi n the slice culture, as determined by ELISA. However, there are striking di fferences in the pattern of A beta ir among the three isoforms of TGF-beta. Isoforms 1 and 3 produced a cellular pattern of AP staining that colocaliz es with GS lectin staining (microglia). TGF-beta 2 produces dramatic A beta staining of pyramidal neurons in layers CA1-CA2. In addition to cellular A beta staining, plaque-like deposits are increased by all of the TGF-beta s . Although no gross toxicity was observed, morphological neurodegenerative changes were seen in the CAI region when the slices were treated with A bet a plus TGF-beta 2. Our results demonstrate important functional differences among the TGF-beta isoforms in their ability to alter the cellular distrib ution and degradation of A beta. These changes may be relevant to the patho logy of Alzheimer's disease (AD).