TrkA pathway activation induced by amyloid-beta (Abeta).

Amyloid-beta (Abeta), a cytotoxic fragment of Amyloid Precursor Protein (APP), has been implicated in the etiopathogenesis of Alzheimer's disease (AD). Since several neurotrophins signalling pathways may be activated in response to toxic insults, we investigated whether a similar response is triggered also by Abeta. After Abeta (25-35) peptide administration to cultured rat hippocampal neurons, the nerve growth factor (NGF) and its receptor (TrkA) mRNA expression is up-regulated. Moreover, we observe an increased cellular TrkA expression (4.5 fold) and NGF release in the culture medium (5-fold). Concomitantly, TrkA, Akt and glycogen synthase kinase 3beta (Gsk3beta) phosphorylation significantly increase. Interestingly, when cells were treated with Abeta (25-35) in the presence of blocking antibody against NGF, only a partial TrkA activation (2-fold) was observed. These results have been confirmed by using pathophysiological Abeta (1-42) oligomers. Our data provide the evidence that Abeta induces the TrkA pathway activation directly by itself and indirectly promoting NGF secretion.